Abstract

Defining Alcohol Consumption and Drinking Patterns

Determining the level of alcohol consumption that is dangerous to a developing embryo or fetus is a complex issue that requires researchers to define the factors influencing peak BACs after any given alcohol consumption. These variables include both the amount consumed and the pattern in which the amount is consumed.

Animal Studies of Consequences of Maternal Drinking Patterns

For many reasons, it is neither ethical nor practical to give alcohol to pregnant women in order to evaluate dose-response effects of alcohol exposure on the developing fetus. In contrast, animal studies enable researchers to control fetal alcohol exposure in terms of size, number, pattern, and timing of alcohol doses given to the mother. Thus, researchers can assign experimental animals (e.g., rats, mice, sheep, and nonhuman primates) to particular groups and administer alcohol to them at specific doses (measured in grams per unit of body weight, such as grams per kilogram [g/kg]) and in specific patterns. This practice ensures uniform dosing (i.e., equal amounts and patterns) for all animals included in the research and, therefore, is suitable for examining issues related to the effects of alcohol exposure on the developing fetal brain, including threshold levels and differences between exposure patterns.

Results of Animal Studies on the Effects of Maternal Drinking Patterns

Animal models have been used extensively to investigate the relationship among alcohol levels, drinking patterns, and brain damage. Several noteworthy studies have systematically examined these research questions using both rats and nonhuman primates. Some of those studies have demonstrated a clear relationship between the alcohol dose and the severity of gross brain growth restriction. In one study that used artificial rearing methods³ (Bonthius and West 1988), groups of newborn rats were exposed daily during the early postnatal period to a wide range of alcohol doses (i.e., 2.5 to 7.5 g/kg/day). The peak BACs ranged from 30 mg/dL to 525 mg/dL⁴ for the various alcohol-treated groups. The investigators found a near-linear inverse relationship between alcohol dose and total brain weight—that is, higher alcohol doses resulted in lower brain weight. Thus, for a given exposure pattern, higher alcohol doses resulted in both higher BACs and more severe injury to the developing brain.

Other findings from the same research group support the hypothesis that binge-like alcohol exposure is more harmful than non-binge exposure. In that study, Pierce and West (1986) compared the effects of equal total amounts of alcohol administered in different exposure patterns on brain growth in rats. Using artificial rearing methods, the researchers exposed groups of neonatal rats to a total alcohol dose of 6.6 g/kg/day, which was administered in two patterns: one group was exposed continuously (i.e., 24 hours per day) to alcohol for several days, resulting in an average peak BAC of 49 mg/dL. The second group received condensed exposure (i.e., only 12 hours per day) for the same number of days, resulting in an average peak BAC of 270 mg/dL. At the end of the treatment period, the brain weights of the rats in the condensed exposure group were significantly lower than those of the continuously exposed group, demonstrating that brain growth is impaired more by bingelike patterns of exposure to alcohol than by continuous exposure.

A subsequent study tested the hypothesis that a lower daily dose of alcohol can result in greater brain growth restriction and cell loss in various brain regions than will a higher daily dose if the lower dose is administered in a binge-like pattern (Bonthius and West 1990). The researchers compared the following three groups of alcohol-exposed neonatal rats:

• One group was exposed to 4.5 g/kg/day in a condensed pattern (i.e., for 4 hours per day); the resulting peak BACs averaged 365 mg/dL.

• A second group was exposed to the same dose administered in a less condensed pattern (i.e., for 8 hours per day), resulting in peak BACs averaging 195 mg/dL.

• A third group was exposed to a higher dose of alcohol (i.e., 6.6 g/kg/day) administered in a continuous pattern (i.e., for 24 hours per day); the resulting peak BACs averaged 45 mg/dL.

When the brains of all animals were weighed at the end of the study, the brain weights of the animals in the group receiving 4.5 g/kg/day over 4 hours were the lowest, followed by the brain weights of the animals receiving 4.5 g/kg/day over 8 hours (see figure). The animals receiving 6.6 g/kg/day administered continuously had the highest brain weights. These results clearly demonstrate that a lower daily dose consumed in a bingelike pattern can be more harmful than a higher daily dose consumed in a continuous pattern. The reason underlying these results is that the condensation of the alcohol administration into progressively shorter periods generated correspondingly higher peak BACs.

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Effects of different patterns of neonatal alcohol exposure on brain development in rats. Newborn rats received alcohol according to three different schedules from day 4 to day 10 after birth. Group A received a total of 4.5 grams of alcohol per kilogram of bodyweight per day (g/kg/day), administered over 4 hours each day. Group B received the same amount of alcohol (4.5 g/kg/day), but it was administered over 8 hours each day. Group C received a total of 6.6 g/kg/day, administered over 24 hours each day. Control animals received no alcohol during that time. The peak blood alcohol concentrations (BACs) for each group are shown in panel A. On day 10, the animals’ total brain weights were measured (panel B). Group A showed the lowest brain weights, whereas the brain weights of group C were almost normal. The results suggest that higher peaks in BAC are associated with greater reductions in brain weight.

This relationship between pattern of alcohol exposure (and, consequently, peak BACs) and brain growth restrictions also has been observed in studies using nonhuman primates as experimental subjects. In an extensive and elegant series of experiments, researchers exposed nonhuman primates to alcohol in a bingelike pattern during different times of fetal brain development. The investigators administered alcohol to pregnant monkeys during gestation using 3 different administration periods: (1) the first 3 weeks, (2) the first 6 weeks, or (3) all 24 weeks of the gestation period (Astley et al. 1999). The monkeys received the alcohol in a binge-like pattern for 1 or 2 days per week (corresponding to a weekend binge), resulting in average peak BACs of 223 mg/dL. The study found that on several indices of gross brain development and cognitive functioning, no difference in the severity of the deficits existed among the infants of monkeys from the three timing groups. Thus, a similar amount of gross brain damage and impairment in cognitive function occurred if the fetuses were exposed to alcohol only during the early part of gestation, rather than throughout gestation.

Similar studies conducted on non-human primates demonstrated a variety of possible outcomes from alcohol exposure during early gestation. These outcomes included the loss of certain neurons (i.e., Purkinje cells) in the cerebellum⁵ (Bonthius et al. 1996), loss of certain neurons in the eye (i.e., retina ganglion cells) combined with various eye malformations (Clarren et al. 1990), and facial abnormalities similar to those seen in FAS children (Astley et al. 1999). Viewed together, these findings clearly demonstrate the vulnerability of the fetal brain to alcohol-induced damage from exposure during early gestation. Clinicians should emphasize these results, as well as those of the rat studies, when informing women of childbearing age about the harmful effects of binge-like alcohol exposure on fetal brain development during the first 4 to 6 weeks of pregnancy. These animal studies undeniably demonstrate that drinking cessation only after a pregnancy is realized may not spare the fetal brain and other organs from harm, including eventual behavior impairments.

Results of Human Studies on the Effects of Maternal Drinking Patterns

Limited information exists on binge drinking and fetal outcome among humans in the clinical literature. One reason for this gap is the way that the information gathered from the human population is measured and categorized (e.g., see Gladstone et al. 1996). For example, measurements often focus on the average or total amount of alcohol consumed, rather than on drinking patterns or the maximum alcohol dose consumed on a single occasion. For example, as mentioned earlier, binge drinkers may consume lower total alcohol amounts than do continuous drinkers, because in actuality, binge drinkers consume fewer drinks. Thus, if consumption is averaged over time (e.g., 1 week or 1 month), a binge drinker’s consumption may be classified as light or moderate, suggesting little risk. Furthermore, some alcohol-intake questionnaires inquire about the typical alcohol intake per occasion, rather than the maximum alcohol intake on a single occasion. Averaging the typical amount of alcohol consumed per occasion during a period of 1 month or 1 year may seriously underestimate the maximum amount of alcohol consumed in a single episode of binge drinking. Averaging may lead to particularly ambiguous results, because some animal studies have reported neuronal loss in the developing brain even after only a single episode of binge exposure (Goodlett and Eilers 1997; Pauli et al. 1995).

Nevertheless, several studies have assessed the effects of maternal drinking patterns on the outcome of human offspring. Some of those studies have failed to find a relationship between binge alcohol consumption and adverse offspring outcome; however, such studies are typically plagued with methodological problems (e.g., see Gladstone et al. 1996).

One detailed series of studies examining the effects of binge exposure on offspring development has been conducted by researchers in the Seattle Longitudinal Prospective Study on Alcohol and Pregnancy under the direction of Dr. Ann Streissguth. In this study, pregnant women were asked to estimate their alcohol consumption in terms of quantity (i.e., how much alcohol they drank), frequency (i.e., how often they drank alcohol), and variability (i.e., when they drank alcohol relative to the stages of pregnancy) for two time periods—at midpregnancy and during the month prior to pregnancy recognition (Streissguth et al. 1989). This approach enabled the researchers to calculate scores that reflected both the level and pattern of alcohol consumption. Then, the children of those women were followed for at least 14 years and were assessed at specific ages on several different tasks that reflected learning, memory, and various forms of cognitive processing.

When the children were studied at age 7.5, maternal binge drinking (i.e., consumption of five or more drinks per occasion) in the month prior to pregnancy recognition was the best predictor of neurobehavioral deficits in attention, memory, and cognitive processing as well as inflexibility in problem-solving. Moreover, the children exposed to binge drinking before their mothers realized that they were pregnant were more likely to be rated by their parents as having learning problems, being below average academically, and being hyperactive and impulsive. The children also were more likely to be rated by teachers as expressing behaviors that were incompatible with learning (Streissguth et al. 1990). It is particularly important to note that the commonly used measure of alcohol consumption—average ounces of alcohol consumed per day and frequency of drinking—did not predict these neurobehavioral outcomes.

When the children were studied again at age 11, children of binge-drinking mothers were still classified as having problems with distractibility, restlessness, and lack of persistence (Olson et al. 1992). Finally, when the children reached age 14, the variable “number of drinks per occasion” still significantly predicted some critical neurobehavioral measures (i.e., problems with response inhibition and fluctuating attention span) (Streissguth et al. 1994b). Thus, one common theme emerged from this comprehensive data analysis—the greater the average number of drinks that the pregnant women consumed per occasion, the worse her children later performed on measures important for reading and arithmetic skills (Streissguth et al. 1994a).

The harmful effects of bingelike drinking patterns were confirmed with more recent data from a sample of mothers and their infants studied in Detroit, Michigan (Jacobson et al. 1998). The investigators found that infants born to mothers who consumed at least five drinks per occasion and, on average, at least once per week, had clearly definable functional deficits as measured by birth weight, the Bayley Mental and Psychomotor Developmental scales, the Elicited Play test, and tests of processing speed. The researchers calculated that the threshold for these effects was an average consumption of 0.50 ounces of absolute alcohol per day when the alcohol was consumed in a bingelike fashion. The functional deficits were not observed, however, in the offspring of women who reported drinking frequently but not in a bingelike pattern.

Why is Binge Drinking More Harmful Than Other Drinking Patterns?

Several factors may help explain why binge drinking is particularly harmful to fetal brain development. First, the peak BACs achieved with this drinking pattern are higher than the peak BACs achieved with more continuous drinking patterns. In turn, a high BAC is a critical factor in producing fetal brain injury. Researchers do not yet know the minimum amount of alcohol that is harmful to the developing brain. It is possible that the fetus can tolerate a certain level of alcohol exposure with no ill effects, and that only by binge drinking, a woman would risk exceeding such a threshold for alcohol-induced fetal brain injury. Another consequence of higher peak BACs is prolonged alcohol exposure. The rate of alcohol breakdown (i.e., metabolism) in the body remains the same regardless of the amount of alcohol consumed. As a result, the higher the BAC is, the longer it takes the body to metabolize all the alcohol. Accordingly, binge-drinking episodes produce longer periods of alcohol exposure for the developing fetal brain than do consumption and metabolism of a single drink.

Second, the timing of binge-drinking episodes relative to key stages of brain development may influence the extent of its adverse effects. Binge drinking may be particularly harmful if it occurs at a point in development that is critical for some specific developmental brain event. Because some of these developmental events are of short duration, a single binge-drinking episode might overlap with one of these events. Unfortunately, the prevalence of bingelike alcohol consumption is particularly high among women (and men) of reproductive age; moreover, researchers have found a strong association between binge drinking and unplanned or unprotected sexual activity (Wechsler et al. 1994; Parker et al. 1994). Consequently, binge drinking may increase episodes of unprotected sexual intercourse and, thus, increase the risk of alcohol exposure near conception.

Third, alcohol consumption in a bingelike pattern exposes the developing fetal brain to not only high peak BACs, but also to periods of withdrawal from alcohol. The effects of multiple withdrawal episodes may be a potentially important risk factor for developmental brain injury. To date, no comprehensive studies have examined in detail the effects of oral, bingelike alcohol exposure and the resulting withdrawal during key stages of fetal brain development. Some of the deficits in brain function observed in affected children, however, may be related to severe physiological responses to the withdrawal from alcohol as well as to the exposure to alcohol. This hypothesis is an underrepresented and important area of research that requires further attention.

Conclusions

The evidence presented in this article allows for two critical conclusions. First, the data from the comprehensive series of studies performed on humans, as well as on nonhuman primate and rodent experimental models, clearly show that binge drinking is more harmful to fetal brain development than is non-binge drinking. Second, early alcohol exposure (i.e., during the first few weeks of gestation in humans) may have as much adverse effect on fetal brain development as would alcohol exposure throughout pregnancy. Based on these findings, one might argue that women who engage in binge drinking during the early part of their pregnancy could continue to drink without further consequence. This assumption is incorrect, however, because some aspect of development or cognition that is not measured in the cited studies would most likely be impaired to a greater extent by continuous alcohol exposure throughout pregnancy than by limited exposure during early pregnancy.

Because no threshold for alcohol’s detrimental effects on the developing fetal brain has been established, women should cease to consume alcohol immediately upon learning that they are pregnant. It would be best (i.e., safest), however, that women who are contemplating pregnancy consider changing their drinking habits even before conception. Accordingly, appropriate educational efforts should be directed especially toward young women, who may engage in binge-drinking patterns that can lead to unprotected sexual intercourse and unplanned pregnancies (although men may be held equally accountable for the prevention of unplanned pregnancies). Fortunately, most women reduce or stop their alcohol consumption as soon as they realize that they are pregnant; in some cases, however, some injury to the fetal brain may have already occurred. Even if a mother drank heavily during parts of her pregnancy, abstinence during the remainder of the pregnancy is likely to have beneficial effects on the developing fetus.

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