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PubMed1991

The effects of prenatal alcohol on the central nervous system.

Prenatal alcohol exposure has a profound effect on the developing brain. In fetal alcohol syndrome (FAS), mental retardation and microcephaly are commonly observed. A partial syndrome, fetal alcohol effects (FAE) can result in neurobehavioral sequelae, which may present at birth or appear later in development. This chapter discusses the clinical evidence supporting the concept of FAE, the range of cognitive disturbances seen in FAS and FAE children, and studies on long-term outcome. We review studies that suggest that even in the absence of the stigmata of FAS, neonatal signs of central nervous system dysfunction may predict later developmental deviation. However, the clinical research on the cognitive and behavioral disorders in the FAE population is limited. Examination of electroencephalograms, evoked potentials, and sleep pattern provide additional evidence that the functional integrity of the brain has been altered. An abbreviated review of behavioral animal studies provides additional support for the clinical investigations presented.

Alcohol Drinking↗

PubMed1995

Isolated hyperechoic fetal bowel: significance and implications for management.

OBJECTIVE: The objective of this study was to determine the significance of isolated hyperechoic fetal bowel. STUDY DESIGN: Forty-five cases with prospective, ultrasonographic diagnosis of isolated hyperechoic fetal bowel were reviewed. Fetal variables, including aneuploidy, deoxyribonucleic acid studies for cystic fibrosis, congenital infection, growth retardation, and intrauterine death were reported. RESULTS: Thirty-four of the 45 cases (76%) resulted in live-born infants without detected abnormalities. However, hyperechoic bowel was associated with cystic fibrosis in two cases (4%), congenital infection in two cases (4%), and fetal alcohol syndrome in one case. Termination of pregnancy was elected in three cases and intrauterine fetal death occurred in three cases (7%). Growth retardation was observed in five of 39 (13%) live-born infants. CONCLUSION: Isolated hyperechoic fetal bowel is associated with significant pathologic disorders. Women whose fetuses are diagnosed as having isolated hyperechoic bowel should be offered additional prenatal diagnostic options, including maternal serologic studies for congenital infection, fetal karyotype, and deoxyribonucleic acid testing for cystic fibrosis. In addition, continuing ultrasonographic evaluation of fetal growth and antenatal biophysical assessment should be considered.

Cystic Fibrosis↗

PubMed2000

Antenatal brain injury: aetiology and possibilities of prevention.

Although the aetiology of antenatal brain injury is often unclear, procedures can be employed to prevent or reduce the risk of injury. Defective neuropore closure can be prevented by periconceptional administration of folic acid, and the incidence of other severe malformations and genetic disorders can be reduced by early identification and termination of pregnancy. Antenatal identification of IUGR, administration of corticosteroids to cases with pending preterm birth, and treatment of maternal/fetal infections would also reduce the incidence of injury. Mothers can decrease the risk of injury by maintaining a good diet, avoiding smoking, alcohol intake and exposure to TORCH infections during pregnancy.

Anti-Inflammatory Agents↗

PubMed2004

Workshop on Alcohol Use and Health Disparities 2002: a call to arms.

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) of the National Institutes of Health (NIH) sponsored a "Workshop on Alcohol Use and Health Disparities 2002: A Call to Arms," on December 5, 2002, in Bethesda, Maryland, USA. This workshop was part of the NIAAA/NIH comprehensive strategic plan to reduce, and ultimately eliminate, health disparities. Eleven topics were addressed: (1). biomedical risk factors that may contribute to disparities in the toxic effects of alcohol; (2). alcohol and gene-environment interactions that affect the health of diverse groups; (3). alcohol pharmacogenetics in Mexican-Americans; (4). determinants of risk for alcoholism in minority populations; (5). consideration of population groups in linkage-disequilibrium studies to identify genes associated with alcohol dependence; (6). interaction between alcohol dependence and African-American ethnicity in disordered sleep, nocturnal cytokines, and immunity; (7). disparities of brain functional reserve capacity affecting brain morbidity related to substance abuse; (8). alcohol and pregnancy disparities; (9). role of alcohol in cancer risk disparities; (10). ethnic diversity in alcoholic cardiomyopathy; and (11). postmenopausal health disparities. On the basis of these presentations, seven conclusions emerged: (1). Genetic variations in alcohol-metabolizing enzymes exist in various populations. (2). These enzymes play a role in the variation in health effect outcomes seen in different populations, owing to alcohol consumption. (3). Differences between and among population groups can be critically important for the design and interpretation of studies in genetics. These include differences in expression of phenotype, in locus heterogeneity, in risk alleles, and in population structure. (4). Incidence rates for fetal alcohol syndrome and fetal alcohol spectrum disorders are greater in African-Americans and Native-Americans than in Caucasians. Genetic polymorphisms, nutrition, and other factors may account for these differences. (5). The highest mortality rate for cirrhosis has been found in white Hispanic men. (6). Mexican-Americans have a low frequency of the protective alleles ADH1B(*)2 and ALDH2(*)2 and a relatively high frequency of CYP2E1 c2, which is associated with early onset alcoholism. (7). The incidence rate for cancer is greater for African-Americans than for Caucasians, and part of the higher risk may be attributed to heavier drinking.

Alcohol Drinking↗

PubMed2005

[Fetal injury and alcohol drinking during pregnancy].

BACKGROUND: There is still an ongoing discussion whether moderate alcohol consumption during pregnancy is harmful to the fetus. In most western countries, however, total abstinence is recommended. MATERIAL AND METHODS: Over the last five years we have seen 64 infants and children with alcohol-related disorders. We present the clinical records of one alcohol-damaged child, and present the latest recommended categorisation of alcohol-related disorders in infants and children. RESULTS: In our experience, some women with heavy alcohol consumption are allowed to continue their abuse without interference from health professionals. Children of women with moderate alcohol consumption may be seriously damaged. Updated research on pregnancy and alcohol that we have reviewed provide clear evidence that brain structure as well as brain function are affected by heavy prenatal alcohol exposure. INTERPRETATION: Use of alcohol in pregnancy, also in moderate amounts, is a serious risk factor for fetal damage. Therefore complete abstinence from alcohol during pregnancy should be recommended. For the alcohol-damaged children, early recognition and appropriate treatment will give the child a better opportunity for future optimal development.

Abnormalities, Drug-Induced↗

PubMed2005

Different adaptations in ventral tegmental area dopamine neurons in control and ethanol exposed rats after methylphenidate treatment.

BACKGROUND: Methylphenidate (MPH) is a psychostimulant effective in treating attention-deficit/hyperactivity disorder (ADHD). Repeated MPH treatment may increase substance abuse risk because of adaptations in dopaminergic (DA) function associated with sensitization to subsequent stimulant exposure. However, this possibility is based on observations in normal animals and may not apply to animals with attention problems linked to compromised DA function such as prenatal ethanol exposed (PE) animals. METHODS: The electrical activity of ventral tegmental area (VTA) DA neurons was studied after the cessation of repeated MPH treatment at a threshold dose (1 mg/kg/day for 3 weeks) in PE and control rats. RESULTS: In control rats, there was a continuous increase in VTA DA neuron excitability post-MPH treatment, characterized by a transient increase in population activity (1 day posttreatment) followed by decreased population activity (30-60 days posttreatment) in most of the animals due to depolarization inactivation. In PE rats, MPH treatment decreased the excessive excitability of VTA DA neurons and resulted in prolonged normalization in the population activity (1-60 days posttreatment). These changes were not mediated by altered sensitivity of somatodendritic DA autoreceptors. CONCLUSIONS: Repeated MPH treatment produced distinctly different effects on VTA DA neuron activity in control and PE animals. These results suggest that repeated MPH treatment for ADHD may not lead to increased substance abuse risk in special populations such as individuals with fetal alcohol spectrum disorder.

Action Potentials↗

PubMed2005

N-methyl-D-aspartate subunit expression during mouse development altered by in utero alcohol exposure.

OBJECTIVE: Alcohol-related neurodevelopmental disorders are contributors to long-term learning disabilities. By using a model for fetal alcohol syndrome, we have shown that prenatal alcohol exposure results in adult learning deficits of unknown mechanisms. In the developing hippocampus, the N-methyl-D-aspartate (NMDA) receptor subunit NR2B triggers long-term potentiation, fundamental to learning and memory; this is supplemented by the less plastic NR2A subunit in the adult. To understand the mechanism of learning deficits in FAS, we evaluated NR2B and NR2A expression in embryonic and adult mice. STUDY DESIGN: Pregnant C57Bl6/J mice were treated on gestational day 8 with alcohol or control (saline solution). Embryos were harvested at 6 hours, 24 hours, and 10 days, and brains from adult offspring were collected at 3 months (after evaluation for learning deficit). Calibrator-normalized relative real-time polymerase chain reaction was performed for NR2B and NR2A with glyceraldehyde-3-phosphate dehydrogenase standardization. Statistical analysis included analysis of variance. RESULTS: At 6 hours, NR2B expression in the alcohol-exposed embryos was higher than in controls (P < .01). NR2A was not expressed in either group. By 24 hours there was no difference in NR2B (P = .3). However, at 10 days NR2B was lower in alcohol-exposed animals (P = .02). In the adult brains there was a relative decrease in NR2B (P = .03) and an increase in NR2A (P < .01). CONCLUSION: Prenatal alcohol exposure during development induces NR2B expression deregulation in the embryos that persists until adulthood, when a relative increase in the less modifiable subunit NR2A occurs. This alteration in NMDA receptor subunits may underlie the learning abnormalities in fetal alcohol syndrome.

Animals↗

PubMed1996

Maternal phenylketonuria: a metabolic teratogen.

The maternal phenylketonuria (PKU) syndrome refers to the teratogenic effects of PKU during pregnancy. These effects include mental retardation, microcephaly, congenital heart disease, and intrauterine growth retardation. In untreated pregnancies wherein the mother has classic PKU with a blood phenylalanine level > or = 1,200 microM (20 mg/dl), the frequencies of these abnormalities in offspring are exceedingly high, approaching 75-90% for microcephaly and mental retardation and 15% for congenital heart disease. There is a dose response relationship with progressively lower frequencies of these abnormalities at lower phenylalanine levels, both in the pregnancies of women with variants of PKU and in treated classic PKU pregnancies. The pathogenesis of this syndrome is unknown; it may be related to inhibition by phenylalanine of large neutral amino acid transport across the placenta or to direct toxicity of phenylalanine and/or a phenylalanine metabolite in certain fetal organs. A mouse model for PKU now exists, and studies of maternal PKU in this model are in progress. The treatment of maternal PKU consists of biochemical control through a phenylalanine restricted diet during pregnancy. The best results are obtained with diet initiation before conception or no later than the earliest weeks of pregnancy. Women with PKU and their families require much psychosocial support to meet the strict requirements of a maternal PKU pregnancy, including compliance with a difficult diet. With such compliance, however, it seems that bearing normal or near normal offspring is possible.

Abnormalities, Multiple↗

PubMed2000

Experimental study of umbilical cord length as a marker of fetal alcohol syndrome.

Umbilical cord length has long been investigated as a potential marker of intrauterine events that may place the neonate at risk for future adverse developmental sequelae. Experimentally, significantly shortened cords have been reported in association with prenatal exposure to common drugs of abuse. This study in rats reports the time course of effects on umbilical cord length of a daily maternal ethanol gavage (3,200 mg/kg) from gestational day 6 through termination of pregnancy at either day 17, 18, 19, or 20. A total of 786 fetuses derived from 60 litters were examined. Control fetuses demonstrated a linear increase in umbilical cord length and body weight gain during late gestation, findings that support previous studies. The body weights of the ethanol-exposed fetuses were reduced significantly on all gestational days examined, indicating intrauterine growth retardation, a characteristic of fetal alcohol syndrome. Similarly, acute fetal akinesia as well as long-term sequelae stemming from impaired neurological development would result from the elevated blood ethanol levels achieved in this study. The umbilical cords of ethanol-exposed fetuses were significantly shorter on gestational days 19 and 20 in comparison to their controls, while cord lengths on days 17 and 18 were not shortened significantly. A stretch hypothesis has been proposed suggesting that the degree of fetal activity is the main determinant of umbilical cord length. In rats, there is a physiologic diminution of the volume of amniotic fluid (oligohydramnios) in late gestation (day 19 to term), which restricts fetal movements but does not appear to alter the linear relationships between gestational age and cord length in controls, thus arguing against the stretch hypothesis. However, cord lengths in the ethanol-exposed fetuses plateaued in late gestation, suggesting possible adherence to a stretch hypothesis. This dichotomy is discussed emphasizing fetal growth and activity as well as intrauterine space.

Abnormalities, Drug-Induced↗

PubMed1992

Congenital defects of the limbs and alcohol exposure in pregnancy: data from a population based study.

Limb deficiency may occur in offspring prenatally exposed to alcohol. In a study on limb deficiency occurring in 1,213,913 consecutive liveborn infants in British Columbia, born in the years 1952-1984, a total of 659 cases with limb deficiency was identified. Cases with documented maternal alcohol abuse in pregnancy in this group were analyzed separately. We found eight cases with severe prenatal alcohol exposure (6 F, 2 M). In six of the eight cases a terminal transverse defect of the forearm or hand was present. In the remaining two cases ulnar defects were identified. These observations give further support to the hypothesis that intrauterine alcohol exposure may cause limb defects. This has also been demonstrated in experimental animals. Terminal transverse defects made up a larger proportion of cases with known alcohol exposure (6/8) than of cases where alcohol exposure was not noted (217/651) (chi 2 = 6.13; P < 0.025) in this study. The defects primarily involved the right hand and forearm. This suggests a vascular origin of the limb defects after intrauterine alcohol exposure.

Abnormalities, Drug-Induced↗

PubMed1993

Quantitation of craniofacial anomalies in utero: fetal alcohol and Crouzon syndromes and thanatophoric dysplasia.

The study of fetal growth and development by ultrasound has been greatly facilitated in the past few years by the availability of anthropometric standards for the fetal body. Thus, the obstetrician is able to discern between normal and grossly abnormal, and even to quantitate certain fine fetal structures such as the face. This paper presents results obtained from a group of 5 patients referred to the Medical Center from private practices in Indianapolis, Indiana. Prenatal cephalometric analyses by ultrasound suggested the presence of craniofacial anomalies in all 5 cases. However, such defects were not detectable by routine ultrasonographic examination. A clinical examination after birth of each of these 5 patients suggested the following diagnoses: Fetal Alcohol Syndrome (FAS) in 2 individuals, Fetal Alcohol Effects (FAE) in one individual, Crouzon Syndrome (CS) in one patient, and Thanatophoric Dysplasia (TD) in one patient. In order to compare the craniofacial measurement values for each patient to normal standards, we developed Z-Score profiles and Pattern Variability Indexes (PVI) as described by Garn et al. [1984, 1985]. The values presented here support the idea that even mildly abnormal fetal craniofacial patterns are detectable by this relatively new application of ultrasound. At the present time, no conclusions can be made regarding the diagnostic accuracy of these patterns and profiles. However, the potential value of fetal cephalometry for documenting craniofacial dysmorphology is clearly indicated.

Cephalometry↗

PubMedDate not supplied

Histological changes in the liver of fetuses of alcohol-treated pregnant rats.

In this study, immunolocalization of tenascin (TN), type IV collagen and histopathological changes in the liver of fetuses of pregnant Wistar albino rats treated with two doses of alcohol (1 and 5 g kg(-1) day(-1)) were determined. The samples of liver obtained from fetuses of rats on day 21 of gestation were evaluated morphologically and fixed for histology and immunohistochemistry. The sections stained with H&E and peroxidase-antiperoxidase (PAP) method for TN and type IV collagen were evaluated and immunohistochemical staining results were examined by the intensity of labelling. Statistical evaluation of data showed that there were no differences in liver weights between the control and calorie control groups; but some differences in relative liver weight between the control and alcohol treatment groups were determined. The changes in the liver histology such as degeneration of the cytoplasm of hepatocytes and increases in the number of megakaryocytes were seen in the fetuses of groups receiving alcohol during pregnancy. Increases in the immunolocalization of TN and type IV collagen in the liver of fetuses of alcohol-receiving rats were also found.

Animals↗

PubMed1988

Flow cytometric and histological analysis of mouse thymus in fetal alcohol syndrome.

Reduced thymus size and fetal weight were seen in 18-day old fetuses of C57BL/6 female mice fed a complete liquid diet containing 25% ethanol-derived calories (EDC) from gestational day 0 to 18. Thymocytes from fetuses from the 25% EDC diet group and from pair-fed and ad-lib control diet groups were compared by flow cytometry for expression of thymocyte differentiation antigens. The proportions of L3T4-positive and Lyt-2-positive thymus cells were significantly reduced in alcohol-exposed fetuses compared to controls; however, the number of Thy-l-positive cells did not differ among any of the groups. Histologically, the thymus from 25% EDC fetal mice failed to show the delineation between cortex and medulla that was seen in the thymuses of control fetuses. These results indicate that thymus immaturity is one of the accompanying features of fetal alcohol syndrome.

Animals↗

PubMed1984

The effects of high dose sporadic (binge) alcohol intake in mice.

BALB/c and CBA/h mice were used to investigate the teratogenic effects of sporadic high doses of ethanol. Two consecutive days between days 8 and 11 of organogenesis were chosen on which to administer 0.5 ml of 20 percent ethanol by gavage. An additional group was similarly dosed for four consecutive days starting on the eighth day. All the mice were killed on day 18 of gestation and evidence of growth retardation and malformation in the offspring was sought by skeletal and soft tissue screening. The basic pharmacokinetics of ethanol intake were also investigated. The most marked effects of ethanol were an increase in resorptions, skeletal growth retardation and skeletal variants, however all appeared to be strain specific. The results confirm that ethanol is embryotoxic and suggest that animal models are appropriate for studying aspects of growth retardation.

Alcohol Drinking↗

PubMed1979

Prenatal ethanol exposure in mice: teratogenic effects.

C57BL/6J mice were fed a liquid diet in which 17, 25, or 30% of the calories were derived from ethanol from the fifth through the tenth day of gestation. Control mice were fed lab chow or pair-fed identical diets, except that sucrose substituted isocalorically for ethanol. At term the fetuses were removed and, following fixation, examined by microdissection. The incidence of fetal resorptions and congenital malformations increased in a dose-related manner. Anomalies included skeletal, neurological, urogenital, and cardiovascular systems. These data indicate that in mice, an alcohol diet which is adequate in vitamins and protein results in increased fetal wastage and birth defects.

Abnormalities, Drug-Induced↗

PubMed1993

Developmental changes in the optic nerve related to ethanol consumption in pregnant rats: analysis of the ethanol-exposed optic nerve.

Visual impairment is one of the most common ophthalmic abnormalities in fetal alcohol syndrome. Pathologic changes in optic nerve development related to alcohol consumption could be involved in this dysfunction. In order to assess the consequences of pre- and postnatal exposure to alcohol on the developing optic nerve, we administered an ethanol-containing liquid diet (5% w/v) before and during gestation and throughout lactation to rats and their offspring. A group of control animals were kept on a pair-fed isocaloric diet. The optic nerves were obtained at key stages from fetuses (21 days of gestation) and pups (4, 7, 14, 21 and 28 postnatal days). Samples of the optic nerve cross-section, behind the eyeball, were processed for analysis of gliogenesis, myelinogenesis, axonal growth, and remodelling events, using light and electron microscopy. Qualitative, morphometric, and immunocytochemical analyses, alternatively using anti-GFAP and anti-MBP antibodies, were carried out. Optic nerve cross-sections from prenatal and postnatal alcohol-exposed rats showed a decrease in size. Ultrastructural alterations and retarded development in macroglial cells, optic axons, and myelin sheath were also observed. The most prominent abnormalities were: damage of cytoplasmic organelles and disorganization of cytoskeleton in astrocytes; a decrease in free ribosome density and nuclear membrane inclusions in oligodendrocytes; and fragmentation of lamellae, aberrant myelin sheaths and intralamellar inclusions in myelin. These findings suggest that alcohol abuse during pregnancy is teratogenic to the optic nerve and closely related to the altered visual function.

Abnormalities, Drug-Induced↗

PubMed1994

Optic nerve hypoplasia: comparative effects in children and rats exposed to alcohol during pregnancy.

Children with the fetal alcohol syndrome often have ocular anomalies. These include abnormalities of the eyes and adnexa (strabismus, blepharoptosis, epicanthus), as well as intraocular defects (cataract, glaucoma, persistent hyperplastic primary vitreous, retinal and optic nerve anomalies). Based on the clinical results in an ophthalmological study of a group of Swedish children with the fetal alcohol syndrome, in which optic nerve hypoplasia was found in up to one-half of the group, an experimental study was designed in rats pre- and perinatally exposed to alcohol by means of a liquid diet. The optic nerve was seriously affected. Macroglial cells and optic axons were ultrastructurally damaged. The diameter of the optic nerve cross section, glial cell nuclear area, axonal diameter, and the total number of optic axons showed significantly lower values in the alcohol-exposed group than in the controls. In addition, the retina from the alcohol-exposed animals displayed significantly lower values of the retinal thickness and ganglion cell nuclear volume, as compared to the controls. Thus, rats exposed to alcohol in utero developed hypoplasia of the optic nerve similar to the findings in children born to alcoholic mothers. This strongly supports the hypothesis that prenatal alcohol exposure may adversely affect the development of the optic nerve.

Animals↗

PubMed1988

Maternal ethanol use and selective fetal malnutrition.

Maternal ethanol ingestion may cause fetal injury, particularly impaired somatic and brain growth, by at least two mechanisms: (1) directly, by fetotoxicity from ethanol and/or acetaldehyde; (2) indirectly, by ethanol-induced placental injury and selective fatal malnutrition. There is ample evidence that ethanol and/or acetaldehyde is fetotoxic. In addition, alcoholics are frequently in a state of poor nutrition. However, regardless of maternal nutritional status, ethanol can be placentotoxic, impairing the normal transfer of essential fetal nutrients. Ethanol and/or acetaldehyde has been shown to inhibit placental uptake and/or transfer of amino acids, zinc, and glucose. These effects have been evaluated in animal models and in human tissue. Recent use of the isolated perfused human placental cotyledon has begun to delineate the pathophysiology of ethanol-induced placental injury.

Animals↗