Fetal Alcohol Effects Research Articles

Biochemical markers of alcohol use in pregnant women

Objectives To describe the serious health consequences of alcohol (ethanol) use, especially as they relate to pregnancy and the development of fetal alcohol syndrome (FAS) and fetal alcohol effects (FAE). The classic markers of alcohol exposure, including blood/breath alcohol, γ-glutamyl transferase (γGT), mean corpuscular volume (MCV), hemoglobin-associated acetaldehyde (HAA) and carbohydrate deficient transferrin (CDT), are valuable and their methods of analysis are reviewed. Conclusions Since both FAS and FAE represent two of the leading preventable causes of mental retardation and birth defects, identification of alcohol use early in pregnancy is important to avoid adverse fetal outcomes. Unfortunately, the diagnosis of FAS and FAE is usually made after birth, when alcohol damage has become irreversible and permanent. The clinical laboratory can help prevent this damage and make a valuable contribution in assessing prenatal alcohol use. The clinical utility of blood/breath alcohol, γGT, MCV, HAA and CDT in alcohol use identification, especially in pregnancy, is substantial. Although none of the markers singularly has adequate sensitivity and specificity for screening, their diagnostic utility increases when measured as a panel. This is especially true in detecting alcohol use in pregnancy where the presence of several positive markers was correlated with the presence of alcohol-related fetal effects.

Learning following prenatal alcohol exposure: performance on verbal and visual multitrial tasks

Verbal Learning deficits have been reported following prenatal alcohol exposure (PAE). This study examined verbal and visual multitrial learning in children with fetal alcohol syndrome (FAS) or fetal alcohol effects (FAE) and controls matched on age and gender from the same community. In this study, the FAS/FAE group’s immediate memory on the Verbal Learning and Visual Learning tasks from the Wide Range Assessment of Memory and Learning (WRAML) was significantly weaker than that of the control group. Although the FAS/FAE group also recalled significantly less information after a delay, they did retain an equivalent proportion of the visual and verbal information as compared to the control group. Thus, the overall pattern of performance on both verbal and visual measures was consistent with that observed in previous studies of Verbal Learning: despite weaker learning, the FAS/FAE group’s relative retention of information was no different than that of controls.

Learning following prenatal alcohol exposure: performance on verbal and visual multitrial tasks

Verbal Learning deficits have been reported following prenatal alcohol exposure (PAE). This study examined verbal and visual multitrial learning in children with fetal alcohol syndrome (FAS) or fetal alcohol effects (FAE) and controls matched on age and gender from the same community. In this study, the FAS/FAE group's immediate memory on the Verbal Learning and Visual Learning tasks from the Wide Range Assessment of Memory and Learning (WRAML) was significantly weaker than that of the control group. Although the FAS/FAE group also recalled significantly less information after a delay, they did retain an equivalent proportion of the visual and verbal information as compared to the control group. Thus, the overall pattern of performance on both verbal and visual measures was consistent with that observed in previous studies of Verbal Learning: despite weaker learning, the FAS/FAE group's relative retention of information was no different than that of controls.

Prevalence of fatty acid ethyl esters in meconium specimens.

Fetal alcohol syndrome (FAS), alcohol-related birth defects (ARBDs), and alcohol-related neurodevelopment disorders (ARNDs) in neonates are often the result of maternal alcohol consumption during pregnancy. Facial characteristics are associated with FAS, but ARBDs and ARNDs are more difficult to diagnose. Fetal exposure to alcohol can cause central nervous system dysfunction, pre- and postnatal growth problems, cardiac defects in neonates, and attention deficit disorders and mental retardation in older children. To date, diagnosis of fetal alcohol effect has depended largely on maternal interview, although clinical tests are becoming more widely used. Fatty acid ethyl esters (FAEEs) are formed in the body by esterification of ethanol with free fatty acids and trans-esterification of glycerides and have been detected in the meconium of newborns. This report estimates the prevalence of fetal alcohol exposure in two populations by detecting FAEEs in meconium. We analyzed the prevalence of FAEEs in the meconium of two separate groups of neonates by use of solid-phase extraction and analysis by gas chromatography-mass spectrometry in the chemical ionization mode. In the first study, meconium samples were taken anonymously from babies born in a large, regional perinatal center in Hawaii. In the second study, specimens were obtained from infants admitted to six different newborn intensive care units within the state of Utah. In the first study, 73 of 436 (16.7%) meconium specimens tested were considered positive for FAEEs. When broken down into quartiles, the mean total FAEEs measured were 1,059, 3,133, 6,628, and 62,115 ng/g. In the second study, 35 of 289 (12.1%) specimens were considered positive. When broken into quartiles, the mean total FAEEs were 1,139, 3,067, 7,674, and 50,143 ng/g. The overall FAEE profiles of the two study sets were remarkably similar. In an adequate meconium specimen, a total FAEE concentration >10,000 ng/g may indicate that the newborn has been exposed to significant amounts of alcohol during pregnancy.

Alcohol dehydrogenase 2 genotypes, maternal alcohol use, and infant outcome

Objective: To determine whether different alleles of the ADH2 gene (ADH2-1, ADH2-2 and ADH2-3) with differing levels of enzymatic activity can alter the risk of fetal alcohol effects. Study design: ADH2 genotypes were performed on 404 pregnant high-risk women and 139 infants as part of a larger study of alcohol use in pregnancy. Mothers were interviewed about alcohol use during pregnancy, and their infants were examined for alcohol-related features without knowledge of the exposure status. Results: The ADH2-1/3 genotype was more prevalent among black women (46%) than expected (33%); the rate among white women was low as expected (2%). More black women who reported high alcohol use during the pregnancy had the ADH2-1/3 genotype compared with those who reported no alcohol use (70% vs 44%). Sixty percent of the affected black infants had the ADH2-1/3 genotype compared with 29% of the unaffected infants (P <.045). The maternal genotype correlated with her chance of having an infant with alcohol-related physical features (odds ratio = 2.49). This association remained significant after accounting for confounders, such as smoking and maternal weight gain. Alcohol exposure was not significantly associated with infant outcome in black infants after accounting for genotype, smoking, and maternal weight gain, but this association could only be tested in 10 infants of mothers with high exposure. Conclusion: Women with the ADH2-1/3 genotype may be at greater risk for having an affected infant, which may be the result of greater ingestion of alcohol. (J Pediatr 2002;141:780-5)

Is genotype important in predicting the fetal alcohol syndrome?

Is genotype important in predicting the fetal alcohol syndrome?

Midline corpus callosum is a neuroanatomical focus of fetal alcohol damage.

Prenatal exposure to high levels of alcohol often induces birth defects that combine morphological stigmata with neurological or neuropsychological deficits. But it has proved problematic to diagnose these syndromes in adolescents and adults, in whom the morphological signs are absent or attenuated, the behavioral deficits nonspecific, and the exposure history often difficult to reconstruct. Localizing the associated brain abnormalities might circumvent most of these difficulties. To this end, three-dimensional (3D) locations were recorded for 67 homologous points on or near the corpus callosum in magnetic resonance (MR) brain images from 60 adolescents and adults who were normal, 60 diagnosed with fetal alcohol syndrome, and 60 diagnosed with fetal alcohol effects. We combined the standard statistical approach to this type of geometric data, Procrustes analysis, with a multivariate strategy focusing on differences in variability. In this data set, the shape of the corpus callosum and its vicinity proves systematically much more variable in the alcohol-affected brains than in those of the normal subjects. From this excess variability follows a promising classification rule, having both high sensitivity (100 out of 117) and high specificity (49 out of 60) in this sample. The discrimination uses four landmark points and two summary scores of callosal outline shape. The information from the corpus callosum and vicinity, as viewed in MR brain images of full-grown subjects, may serve as a permanent record of the prenatal effects of alcohol, even in patients who are first suspected of these syndromes relatively late in life or who lack the facial signs of prenatal alcohol damage. The statistical pattern underlying the callosal diagnosis also leads to speculations on mechanisms of the prenatal damage.

MRI findings in children with school problems who had been exposed prenatally to alcohol.

This study examined 17 children (nine males, eight females; mean age 13 years) with prenatal alcohol exposure of various durations. The aim of the study was to detect specific brain morphological alterations by means of MRI and to see if findings correlated with particular cognitive deficits. Of the 17 children, five had been exposed to heavy maternal consumption of alcohol (over 10 drinks/week) during the first trimester only; four had been exposed during the first and second trimester; and eight had been exposed throughout pregnancy. Five children had alcohol related neurobehavioural disorder, seven were diagnosed as having foetal alcohol effects and five were diagnosed as having foetal alcohol syndrome. Hypoplasia of the vermis was observed in 10 children and malformed posterior vermis in one additional child. Five children had hypoplastic cerebellar hemispheres. Hypoplasia of the corpus callosum was observed in two children. Small hippocampi were observed in three children and wide cortical sulci in six. No specific structural anomaly correlated with a particular neuropsychological deficit. In this study, deviations in the development of the vermis was the most sensitive morphological indicator of the effects of prenatal alcohol exposure. It was seen in every diagnostic group including children who had been exposed during only the first trimester of pregnancy.

MRI findings in children with school problems who had been exposed prenatally to alcohol

This study examined 17 children (nine males, eight females; mean age 13 years) with prenatal alcohol exposure of various durations. The aim of the study was to detect specific brain morphological alterations by means of MRI and to see if findings correlated with particular cognitive deficits. Of the 17 children, five had been exposed to heavy maternal consumption of alcohol (over 10 drinks/week) during the first trimester only; four had been exposed during the first and second trimester; and eight had been exposed throughout pregnancy. Five children had alcohol related neurobehavioural disorder, seven were diagnosed as having foetal alcohol effects and five were diagnosed as having foetal alcohol syndrome. Hypoplasia of the vermis was observed in 10 children and malformed posterior vermis in one additional child. Five children had hypoplastic cerebellar hemispheres. Hypoplasia of the corpus callosum was observed in two children. Small hippocampi were observed in three children and wide cortical sulci in six. No specific structural anomaly correlated with a particular neuropsychological deficit. In this study, deviations in the development of the vermis was the most sensitive morphological indicator of the effects of prenatal alcohol exposure. It was seen in every diagnostic group including children who had been exposed during only the first trimester of pregnancy.

Corpus Callosum Shape and Neuropsychological Deficits in Adult Males with Heavy Fetal Alcohol Exposure

Persons with brain damage consequent to prenatal alcohol exposure have typically been diagnosed with either fetal alcohol syndrome (FAS) or fetal alcohol effects (FAE), depending on facial features. There is great variability of behavioral deficits within these groups. We sought to combine neuroanatomical measures with neurocognitive and neuromotor measures in criteria of greater sensitivity over the variety of consequences of alcohol exposure. To this end, midline curves of the corpus callosum were carefully digitized in three dimensions from T1-weighted MR scans of 15 adult males diagnosed with FAS, 15 with FAE, and 15 who were unexposed and clinically normal. From 5 h of neuropsychological testing we extracted 260 scores and ratings pertaining to attention, memory, executive function, fine and gross motor performance, and intelligence. Callosal midline shape was analyzed by new morphometric methods, and the relation of shape to behavior by partial least squares. The FAS and FAE subgroups have strikingly more variability of callosal shape than our normal subjects. With the excess shape variation are associated two different profiles of behavioral deficit unrelated to full-scale IQ or to the FAS/FAE distinction within the exposed subgroup. A relatively thick callosum is associated with a pattern of deficit in executive function; one that is relatively thin, with a deficit in motor function. The two combine in a very promising bipolar discrimination of the exposed from the unexposed in this sample. Thus there is considerable information in callosal form for prognosis of neuropsychological deficits in this frequently encountered birth defect.

Effects of certain prenatal drugs on the fetus and newborn.

1. Robert J. Boyle, MD* 1. *Professor of Pediatrics, University of Virginia Health System, Charlottesville, VA. After completing this article, readers should be able to: 1. Describe the short- and long-term effects of moderate-to-severe alcohol use in pregnancy. 2. List the risks and long-term effects of smoking relative to pulmonary disease, sudden infant death syndrome, and infant intelligence. 3. Characterize the range of anomalies associated with antiepileptic drug use during pregnancy. 4. Describe the risk of Ebstein anomaly following lithium exposure. 5. Describe the effect of angiotensin-converting enzyme inhibitors in the newborn period. Many pregnant women use multiple prescription, over-the-counter, and recreational drugs during their pregnancies. Questions frequently arise from the mother, the mother’s clinician, and the physician caring for the newborn about the potential risks of these agents for the fetus and newborn. Few of these agents have been evaluated prospectively in pregnant women prior to licensure and marketing. Our knowledge of potential risks to the fetus and newborn, therefore, is based on case reports, epidemiologic surveys of exposed individuals, and animal studies. Multiple factors may influence whether a specific drug may affect an individual fetus or newborn and the magnitude of that effect (Table 1). Clearly, not every infant exposed to an individual drug is affected. Likewise, it is important to note that many of these agents are critical to the mother’s health, and discontinuing the drug may place the mother and fetus at higher risk than continuing the drug. The physician also must acknowledge that patients often take medications that were not prescribed specifically for them. These may include over-the-counter medications that the patient does not recall taking, does not understand the active ingredients, or even does not consider a “medication” or “drug.” Or they may be taking medications that they are reluctant to disclose or that were prescribed to another individual. Reluctance to disclose exposures may be especially true of drugs that carry negative social stigmas in …

Fetal Alcohol Spectrum–The Hidden Epidemic in Our Courts

ABSTRACTThis article discusses the basics of Fetal Alcohol Syndrome and Fetal Alcohol Effects (FAS/E): the history, nature, prevalence, causes, and effects of prenatal exposure to alcohol. Some of the unique features of FAS/E are explored, particularly those that make it so hard to spot and those that predispose people to nonproductive or criminal activity. The presentation of FAS/E in Juvenile Court is discussed and put in the context of the multiplicity of factors pertaining to delinquency; finally, innovative interventions, approaches and resources are laid out. Issues surrounding FAS/E as they appear in Family Court are then explored, with emphasis on the intergenerational transmission of this array of conditions and how we might interrupt such transmission.

Diagnostic perspective of fetal alcohol and tobacco syndromes

ABSTRACT Maldevelopment of the brain in offspring whose mothers drank and/or smoked during pregnancy was evaluated using Japanese data. The diagnostic criteria for fetal alcohol syndrome (FAS) or fetal alcohol effects (FAE) revealed that FAS infants exhibited a severer degree of CNS involvement than FAE infants. In addition to the criteria for fetal tobacco syndrome (FTS), we proposed the term “fetal tobacco effects (FTE)” for when the gestational age is less than 37 weeks. Maldevelopment of the brain was not severer in FTS than FTE, to which factors other than smoking causing a reduction in the gestational period, and ones during pregnancy and delivery may contribute. The effects on the CNS of alcohol were more frequent and severer than those of tobacco. CNS involvement was shown to increase with increasing consumption of alcohol or tobacco.

Geometric morphometrics of corpus callosum and subcortical structures in the fetal-alcohol-affected brain.

Although experienced clinicians have been diagnosing fetal alcohol syndrome (FAS) for nearly 30 years, the rest of the spectrum of fetal alcohol damage is not being classified effectively. This article describes a quantification of neuroanatomical structure that may supply a useful discriminator of prenatal brain damage from alcohol. It is demonstrated in a data set of adults of both sexes. Ninety adults (45 males) were examined by magnetic resonance imaging (MRI). These subjects were group-matched for age and ethnicity across three diagnoses: FAS, fetal alcohol effects (FAE), and normals. All FAS and FAE were heavily alcohol-exposed in utero; normals were not. From T(1)-weighted MR brain images, we extracted 3D morphometric representations of shape for 33-landmark point configurations and 40-point outlines of the corpus callosum along its midline (a slightly nonplanar structure). There are striking differences between exposed and unexposed in the statistical distributions of these two shapes. The differences are better characterized by excess variance in the exposed group than by any change in average landmark or outline shape. For each sex, combining the callosal outline data with the landmark data leads to a powerful quadratic discriminator of exposed from unexposed. The discriminating features include the relationship of brain stem to diencephalon, and localized variabilities of callosal outline shape, but not diagnosis (FAS vs. FAE). Statistical analysis of brain shape is a powerful new source of information relevant to fetal alcohol spectrum nosology and etiology. Patients with FAS and FAE do not differ in these brain shape features, but both differ from the unexposed. The aspects of brain shape that are especially variable may be entailed in the underlying neuroteratogenetic mechanisms.

Fetal Alcohol Effects: Mechanisms and Treatment

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chair was Edward P. Riley. The presentations were (1) Does alcohol withdrawal contribute to fetal alcohol effects? by Jennifer D. Thomas and Edward P. Riley; (2) Brain damage and neuroplasticity in an animal model of binge alcohol exposure during the “third trimester equivalent,” by Charles R. Goodlett, Anna Y. Klintsova, and William T. Greenough; (3) Ganglioside GM1 reduces fetal alcohol effects, by Basalingappa L. Hungund; and (4) Fetal alcohol exposure alters the wiring of serotonin system at mid‐gestation, by F. Zhou, Y. Sari, Charles Goodlett, T. Powrozek, and Ting‐Kai Li.

Fetal alcohol effects: mechanisms and treatment.

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chair was Edward P. Riley. The presentations were (1) Does alcohol withdrawal contribute to fetal alcohol effects? by Jennifer D. Thomas and Edward P. Riley; (2) Brain damage and neuroplasticity in an animal model of binge alcohol exposure during the "third trimester equivalent," by Charles R. Goodlett, Anna Y. Klintsova, and William T. Greenough; (3) Ganglioside GM1 reduces fetal alcohol effects, by Basalingappa L. Hungund; and (4) Fetal alcohol exposure alters the wiring of serotonin system at mid-gestation, by F. Zhou, Y. Sari, Charles Goodlett, T. Powrozek, and Ting-Kai Li.

MK-801 Can Exacerbate or Attenuate Behavioral Alterations Associated With Neonatal Alcohol Exposure in the Rat, Depending on the Timing of Administration

Background: We have reported that administration of MK-801, an NMDA receptor antagonist, during ethanol withdrawal in the developing rat attenuates ethanol's adverse effects on behavioral development. In the present study, we altered the timing of MK-801 delivery in relation to the last alcohol dose to determine if its protective effects were specific to the ethanol withdrawal phase. Methods: Five groups of rats were artificially reared and exposed to alcohol in a binge-like manner on postnatal day (PD) 6, producing peak blood alcohol levels of 335 mg/dl that cleared to 0 mg/dl by 33 hours. Four groups received MK-801 at various times after alcohol treatment (0, 9, 21, or 33 hr post-ethanol). The fifth alcohol-treated group received saline. Two artificially reared control groups were included: one was injected with saline and the other injected with 0.5 mg/kg MK-801. Finally, a normally reared suckle control group was also included. Activity level and performance on a spatial discrimination reversal-learning task were evaluated at PD 18 and PD 40, respectively. Results : Administration of MK-801 at the same time as ethanol treatment (0 hr) produced a high rate of mortality. Ethanol exposure on PD6 increased activity level relative to controls. Administration of MK-801 at 0 hr exacerbated this ethanol-induced overactivity, whereas administration of MK-801 at 21 and 33 hr reduced the severity of ethanol-related overactivity. Similarly, ethanol exposure on PD 6 significantly increased the number of errors committed on a spatial discrimination reversal-learning task. MK-801 injections 9 hrs after ethanol exacerbated this effect, whereas MK-801 treatment 33 hrs after ethanol attenuated this effect. Thus, MK-801 administration at the time of ethanol treatment was highly toxic, whereas during the withdrawal period it was protective. Conclusion : These data are consistent with the hypothesis that ethanol exposure in the neonatal rat inhibits the NMDA receptor, producing a subsequent rebound in NMDA receptor activation and possible excitotoxicity during withdrawal. Both the acute inhibitory effects of ethanol and the excitatory effects of withdrawal may contribute to fetal alcohol effects.

MK‐801 Can Exacerbate or Attenuate Behavioral Alterations Associated With Neonatal Alcohol Exposure in the Rat, Depending on the Timing of Administration

We have reported that administration of MK-801, an NMDA receptor antagonist, during ethanol withdrawal in the developing rat attenuates ethanol's adverse effects on behavioral development. In the present study, we altered the timing of MK-801 delivery in relation to the last alcohol dose to determine if its protective effects were specific to the ethanol withdrawal phase. Five groups of rats were artificially reared and exposed to alcohol in a binge-like manner on postnatal day (PD) 6, producing peak blood alcohol levels of 335 mg/dl that cleared to 0 mg/dl by 33 hours. Four groups received MK-801 at various times after alcohol treatment (0, 9, 21, or 33 hr post-ethanol). The fifth alcohol-treated group received saline. Two artificially reared control groups were included: one was injected with saline and the other injected with 0.5 mg/kg MK-801. Finally, a normally reared suckle control group was also included. Activity level and performance on a spatial discrimination reversal-learning task were evaluated at PD 18 and PD 40, respectively. Administration of MK-801 at the same time as ethanol treatment (0 hr) produced a high rate of mortality. Ethanol exposure on PD6 increased activity level relative to controls. Administration of MK-801 at 0 hr exacerbated this ethanol-induced overactivity, whereas administration of MK-801 at 21 and 33 hr reduced the severity of ethanol-related overactivity. Similarly, ethanol exposure on PD 6 significantly increased the number of errors committed on a spatial discrimination reversal-learning task. MK-801 injections 9 hrs after ethanol exacerbated this effect, whereas MK-801 treatment 33 hrs after ethanol attenuated this effect. Thus, MK-801 administration at the time of ethanol treatment was highly toxic, whereas during the withdrawal period it was protective. These data are consistent with the hypothesis that ethanol exposure in the neonatal rat inhibits the NMDA receptor, producing a subsequent rebound in NMDA receptor activation and possible excitotoxicity during withdrawal. Both the acute inhibitory effects of ethanol and the excitatory effects of withdrawal may contribute to fetal alcohol effects.

Can nootropic drugs be effective against the impact of ethanol teratogenicity on cognitive performance?

Rats exposed pre- (PA) and postnatally (PNA) to ethanol at a dose of 1 g/kg for 24 h developed fetal alcohol effects (FAE). This was measured using a condition-reflex method for active avoidance with punishment reinforcement (shuttle-box) in which pronounced learning and memory deficits in 3-month-old rats were found after ethanol exposure ( Vaglenova and Petkov, 1998. Fetal alcohol effects in rats exposed pre- and postnatally to a low dose of ethanol. Alcohol. Clin. Exp. Res. 22(3), 697–703). In the present study the effects of piracetam (Pyramem) at a dose of 600 mg/kg body weight, aniracetam at 50 mg/kg, and meclophenoxate (Centrophenoxine) at 100 mg/kg were studied. The drugs were administered orally during 10 days to separate groups of naive and pre- and postnatally exposed to ethanol rats. All the investigated nootropic drugs showed a significant possibility to alleviate learning and memory disability of rats with FAE. Aniracetam was administered to 1-month-old rats, demonstrating a prolonged (2 months) therapeutic effect, observed in rats aged 3 months. As previously reported ( Vaglenova and Petkov, 1998), between male rats with FAE and controls, 66 and 33% were ‘poor learners’, respectively. In all nootropic treatment groups the percentage of ‘poor learners’ dropped to 28%. The positive effects of piracetam, aniracetam and meclophenoxate suggest that these drugs could be used for both treatment and prophylactic of FAE-connected disturbances of cognition.

Identifying Maternal Self‐Reported Alcohol Use Associated With Fetal Alcohol Spectrum Disorders

The incidence of Fetal Alcohol Syndrome (FAS) has been estimated at 1 to 3 per 1,000 live births. Fetal Alcohol Spectrum Disorders (FASD) (which include FAS) are estimated to occur in about 1 in 100 births. Cessation of drinking during pregnancy can improve the outcome even if the unborn child is already affected. For individuals born with FASD, an early diagnosis appears to be a protective factor against secondary disabilities. A quick screening tool to identify newborn children at risk has been elusive. A simple descriptive presentation is offered that shows where 36 individuals with FASD were found from among the many patterns and amounts of prenatal alcohol use that were reported by a sample of 1,439 pregnant women whose offspring were later examined within the first 7 years of life. Individuals with FASD (i.e., those with FAS, fetal alcohol effects, alcohol-related neurodevelopmental disorder ) were found within two aggregates of alcohol scores that together recommend a set of three to four alcohol questions. Within this derivation sample, one scoring of the questions yields almost 78% sensitivity and 97% specificity for FASD. Another scoring of the same instrument yields 100% sensitivity with 90% specificity. These new data may facilitate early identification of offspring who may be most in need of early intervention, namely those born with FASD.