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Fetal Alcohol Spectrum Disorders
Fetal Alcohol Spectrum Disorders K Shankar, University of Arkansas for Medical Sciences, Little Rock, AR, USA HM Mehendale, University of Louisiana at Monroe, Monroe, LA, USA Ó 2014 Elsevier Inc. All rights reserved.
Background While alcohol has been consumed for centuries, the damaging effects of alcohol on the developing fetus were first recognized only four decades ago. The term fetal alcohol syndrome (FAS) was originally coined in 1973 by Jones and Smith in their seminal article describing the common dysmorphic and developmental problems of children born to mothers known to have consumed alcohol during pregnancy. It is now widely recognized that the toxic effects of in utero alcohol exposure are manifested by a constellation of physical, behavioral, and cognitive abnormalities persisting into adulthood, over a spectrum of conditions commonly referred to as fetal alcohol spectrum disorder (FASD) of which FAS represents the most severe outcome. Also within this spectrum are partial FAS and alcohol-related birth defects, which are diagnoses that require confirmation of maternal alcohol intake and specific birth defects attributable to alcohol. The term fetal alcohol effects was used previously to describe children with some but not all the features of FAS. Despite considerable knowledge and awareness regarding its teratogenic effects, alcohol continues to be the most common malformation-causing chemical ingested during pregnancy. One of every 29 women who know they are pregnant report alcohol consumption. FASD is considered to be the most common preventable cause of mental retardation. In addition to mental retardation, in utero exposure to alcohol results in increased rates of miscarriage, reduced birth weight, growth retardation, and teratogenic effects including birth defects. The annual cost of FASD according to the 10th Special Report to the US Congress on Alcohol and Health was estimated to be $2.8 billion. The prevalence rates of full FAS case definition in the general US population range from 0.2 to 1.5 cases per 1000 live births annually, which still is a surprisingly small proportion given the number of children exposed to alcohol during fetal development. However, estimates for the entire spectrum range from 3 to 10 times the prevalence of full FAS, resulting in thousands of children born affected by prenatal alcohol each year.
individuals. Further, recent studies using diffusion tensor imaging, magnetic resonance spectroscopy, and functional magnetic resonance imaging have shown that prenatal alcohol disrupts development of both gray and white matter, and results in alterations in cerebral blood flow, neurotransmitters, and neuronal activity even in the absence of structural changes in the brain. Most importantly, this research has revealed that brain function anomalies can exist in individuals even in the absence of tell-tale facial dysmorphology present in children and individuals with FAS. Hence, in addition to the classical features defining FAS, more sensitive tools including behavioral and neurodevelopmental tools are needed to diagnose FASD. Estimating the true incidence of FASD has proved to be a major challenge, especially when a reliable history of alcohol ingestion is absent. Screening for such alcohol exposure information has been aided by a number of brief questionnaires such as the T-ACE, TWEAK, and 10-question AUDIT. More recently, there has been an effort to identify biomarkers that can reflect alcohol exposure, as have been used for tobacco and other drugs of abuse. However, alcohol is mainly metabolized into carbon dioxide and water via oxidative metabolism. Nevertheless, nonoxidative metabolites of alcohol elimination, leading to metabolites such as fatty acid ethyl esters, ethyl glucuronide, and phosphatidyl ethanol, have some potential to reflect alcohol exposure over short periods of time. Newer methodologies, including proteomics and metabolomics, are being leveraged to identify such markers of exposure.
Risk Factors for FASD Several risk factors determine the toxic outcome of in utero alcohol exposure. Risk factors suggested include genetic predisposition, marital status, smoking, use of prescribed or over-the-counter drugs and medications, concomitant usage of other drugs of abuse, occupational or environmental exposure to chemicals, socioeconomic status, and adequate nutrition.
Models of FASD Clinical Assessment of FASD Most experts agree on three diagnostic criteria for the clinical assessment of FASD: (1) prenatal or postnatal growth restriction; (2) central nervous system (CNS) effects, including insufficient development of the brain such as microcephaly, agenesis of corpus callosum; and (3) specific craniofacial dysmorphic features. While earlier studies examining neurodevelopmental changes focused on those individuals most affected by prenatal alcohol, recent studies have examined the range of FASD using novel methodologies. Noninvasive imaging studies have revealed and confirmed structural changes, including reduced brain size and disproportionate reductions in basal ganglia and the cerebellum in affected
590
Research using animal models has shown that each of the major characteristics of human FASD, including craniofacial abnormalities, growth deficiency, and abnormalities of the central nervous system, occurs in one of these animal models: mice, rats, chicks, and primates. Because different species and even strains within species show different degrees of vulnerability to alcohol, experimental results must be interpreted with caution. However, most common animal models of FASD (rats and mice) are very similar to humans and their biochemical processes are virtually the same. Research from animal models has also revealed critical time periods of vulnerability that leads to certain FASD abnormalities. For example, in the mouse and chicken embryos, exposure to alcohol during cranial neural
Encyclopedia of Toxicology, Volume 2
http://dx.doi.org/10.1016/B978-0-12-386454-3.00313-4
Fetal Alcohol Spectrum Disorders crest cells development corresponding to the first 3–4 weeks of human gestation resulted in patterns consistent with observed dysmorphologies of cranial structures and craniofacial defects.
How Much Alcohol Is Safe in Pregnancy? There is no safe drinking level of alcohol during pregnancy. Significant controversy surrounds the amount of alcohol that presents a risk to the fetus and whether a single exposure is of greater consequence than a pattern of exposure during development. Results from clinical and animal studies demonstrate that lower levels of alcohol are needed to produce behavioral anomalies than are needed to produce physical effects and that some brain regions are more susceptible than others. FASD is completely preventable by abstinence to alcohol. The American Academy of Pediatrics recommends counseling women of childbearing age about the effects of alcohol on the fetus. In addition, government-required warning labels about the health effects of alcohol are displayed on alcoholic beverages. A study found almost 80% of 7334 women interviewed were aware of the detrimental effects of alcohol, including the high-risk drinkers. However the warning labels had only a modest effect on personal risk perceptions and drinking behaviors, clearly stressing the need for other effective strategies to decrease alcohol consumption during pregnancy. Considering the cost in economic and human suffering imposed by FASD on the child and the family, prevention via abstinence seems to be the most effective way to reduce the incidence of FASD. Identifying high-risk drinkers is an important first step in this process.
Mechanisms of Induction of FASD The mechanisms leading to FASD remain elusive. A single mechanism for the entire spectrum of FASD is unlikely. However alcohol can (1) trigger cell death in a number of ways, causing different parts of the fetus to develop abnormally; (2) disrupt the way nerve cells develop, travel to form different parts of the brain, and function; (3) constrict the blood vessels resulting in interference with blood flow in and out of the placenta, which can hinder the delivery of nutrients and oxygen to the fetus; and (4) form toxic byproducts after its metabolism (such as acetaldehyde and free radicals), which may become concentrated in the brain and contribute to the development of an FASD. Influences of genetic susceptibility and nutrition may be of critical importance. Clearly, simultaneous or prior exposure to other chemicals may influence the mechanisms and the nature and extent of effects. Several mechanisms involving the direct effects of alcohol on neural development and organogenesis have been explored in animal models. Among them are alcohol-induced changes in neural cell proliferation, reduced growth and neurotropic factors, inhibition of cell adhesion molecule L1, increased oxidative stress and production of free radicals, fetal zinc deficiency, altered vitamin A and folate function, impaired placental function, and disruption of retinoic acid. Of special note is the mechanism of alcohol-induced inhibition of the cell adhesion molecule L1, which is involved in neural cell migration. Recent animal studies have shown that
591
NAPVSIPQ, an active fragment of the glial-derived activitydependent neuroprotective protein that antagonizes the alcohol-induced inhibition of L1, also protects from alcoholinduced fetal growth retardation and demise. These studies open an exciting area of potential pharmacological intervention for FASD; however, the efficacy of any such treatments remains unknown in human subjects.
Interventions for Children with FASD The most desirable approach to prevent FASD is eliminating alcohol consumption during an entire pregnancy. A threelevel model of prevention involving components targeted to the general population, to high-risk communities, and to specific individuals at greatest risk, including women who have already given birth to a child with FASD, has been developed. Of these, targeted prevention efforts have been most promising. Despite prevention efforts, many women continue to consume alcohol during pregnancy, leading to children with FASD. Hence, it is critical to identify interventions that reduce the impact of FASD. The CNS disabilities associated with FASD range from affected individuals presenting combinations of deficits in memory, information processing, academic and social impairments, attention and motor deficits, and executive functioning. Early diagnosis and introduction of interventions in children are associated with decreased long-term adverse outcomes. Recent research has evaluated pharmacological interventions (with stimulant medication), educational and learning strategies, and social communication and behavioral strategies to limit the consequences of FASD. Many of these strategies, including virtual reality training, mathematics intervention, neurocognitive rehabilitation, and parent education and training, have been shown to improve learning, cognitive, and behavioral disabilities in children with FASD.
See also: Alcoholic Beverages and Health Effects; Developmental Toxicology; Mechanisms of Toxicity; Neurotoxicity.
Further Reading Behnke, M., Smith, V.C., Committee on Substance Abuse, Committee on Fetus and Newborn, 2013. Prenatal substance abuse: short- and long-term effects on the exposed fetus. Pediatrics 131 (3), e1009–e1024. Bertrand, J., Interventions for Children with Fetal Alcohol Spectrum Disorders Research Consortium, 2009. Interventions for children with fetal alcohol spectrum disorders (FASDs): overview of findings for five innovative research projects. Res. Dev. Disabil. 30, 986–1006. Brocardo, P.S., Gil-Mohapel, J., Christie, B.R., 2011. The role of oxidative stress in fetal alcohol spectrum disorders. Brain Res. Rev. 67 (1–2), 209–225. Burd, L., Blair, J., Dropps, K., 2012. Prenatal alcohol exposure, blood alcohol concentrations and alcohol elimination rates for the mother, fetus and newborn. J. Perinatol. 32 (9), 652–659. Conover, E.A., Jones, K.L., 2012. Safety concerns regarding binge drinking in pregnancy: a review. Birth Defects Res. A Clin. Mol. Teratol. 94 (8), 570–575. Foltran, F., Gregori, D., Franchin, L., Verduci, E., Giovannini, M., 2011. Effect of alcohol consumption in prenatal life, childhood, and adolescence on child development. Nutr. Rev. 69 (11), 642–659. Frost, E.A., Gist, R.S., Adriano, E., 2011. Drugs, alcohol, pregnancy, and the fetal alcohol syndrome. Int. Anesthesiol. Clin. 49 (1), 119–133.
592
Fetal Alcohol Spectrum Disorders
Fryer, S.L., 2012. Another step forward in relating facial and brain dysmorphologies associated with prenatal alcohol exposure. Alcohol. Clin. Exp. Res. 36 (7), 1131–1133. Grant, T.M., Brown, N.N., Dubovsky, D., Sparrow, J., Ries, R., March–April 2013. The impact of prenatal alcohol exposure on addiction treatment. J. Addict. Med. 7 (2), 87–95. Jones, T.B., Bailey, B.A., Sokol, R.J., 2013. Alcohol use in pregnancy: insights in screening and intervention for the clinician. Clin. Obstet. Gynecol. 56 (1), 114–123. Joya, X., Friguls, B., Ortigosa, S., et al., 2012. Determination of maternal-fetal biomarkers of prenatal exposure to ethanol: a review. J. Pharm. Biomed. Anal. 69, 209–222. Kane, C.J., Phelan, K.D., Drew, P.D., 2012. Neuroimmune mechanisms in fetal alcohol spectrum disorder. Dev. Neurobiol. 72 (10), 1302–1316. Kully-Martens, K., Denys, K., Treit, S., Tamana, S., Rasmussen, C., 2012. A review of social skills deficits in individuals with fetal alcohol spectrum disorders and prenatal alcohol exposure: profiles, mechanisms, and interventions. Alcohol. Clin. Exp. Res. 36 (4), 568–576. Malone, M., Koren, G., 2012. Alcohol-induced behavioural problems in fetal alcohol spectrum disorders versus confounding behavioural problems. J. Popul. Ther. Clin. Pharmacol. 19 (1), e32–e40. Martínez, S.E., Egea, G., 2007. Novel molecular targets for the prevention of fetal alcohol syndrome. Recent Pat CNS Drug Discov. 2 (1), 23–35. Montag, A., Clapp, J.D., Calac, D., Gorman, J., Chambers, C., 2012. A review of evidence-based approaches for reduction of alcohol consumption in Native women who are pregnant or of reproductive age. Am. J. Drug Alcohol Abuse 38 (5), 436–443. Möykkynen, T., Korpi, E.R., 2012. Acute effects of ethanol on glutamate receptors. Basic Clin. Pharmacol. Toxicol. 111 (1), 4–13.
Peadon, E., Rhys-Jones, B., Bower, C., Elliott, E.J., 2009. Systematic review of interventions for children with fetal alcohol spectrum disorders. BMC Pediatr. 9 (35). Pruett, D., Waterman, E.H., Caughey, A.B., 2013. Fetal alcohol exposure: consequences, diagnosis, and treatment. Obstet. Gynecol. Surv. 68 (1), 62–69. Ramadoss, J., Magness, R.R., 2012. Vascular effects of maternal alcohol consumption. Am. J. Physiol. Heart Circ. Physiol. 303 (4), H414–H421. Randall, C.L., 2001. Alcohol and pregnancy: highlights from three decades of research. J. Stud. Alcohol 62, 554–561. Streissguth, A.P., O’Malley, K., 2000. Neuropsychiatric implications and long-term consequences of fetal alcohol spectrum disorders. Semin. Clin. Neuropsychiatry 5, 177–190. Thomas, J.D., Warren, K.R., Hewitt, B.G., 2010. Fetal alcohol spectrum disorders: from research to policy. Alcohol Res. Health 33, 118–126.
Relevant Websites http://www.cdc.gov/ncbddd/fasd/documents/calltoaction.pdf – Centers for Disease Control and Prevention. http://www.mdpi.com/2076-3425/3/2/964/pdf – Indiana University-Purdue University Indianapolis publication. http://www.marchofdimes.com/ – March of Dimes. http://pubs.niaaa.nih.gov/publications/arh25-3/175-184.htm – National Institute on Alcohol Abuse and Alcoholism publication. http://pubs.niaaa.nih.gov/publications/10report/intro.pdf – National Institutes of Health.GOV. http://www.fasdcenter.samhsa.gov/documents/WYNK_Effects_Fetus.pdf – Substance Abuse and Mental Health Services Administration.GOV. http://people.uwec.edu/piercech/fas/fas...htm – University of Wisconsin.
Background While alcohol has been consumed for centuries, the damaging effects of alcohol on the developing fetus were first recognized only four decades ago. The term fetal alcohol syndrome (FAS) was originally coined in 1973 by Jones and Smith in their seminal article describing the common dysmorphic and developmental problems of children born to mothers known to have consumed alcohol during pregnancy. It is now widely recognized that the toxic effects of in utero alcohol exposure are manifested by a constellation of physical, behavioral, and cognitive abnormalities persisting into adulthood, over a spectrum of conditions commonly referred to as fetal alcohol spectrum disorder (FASD) of which FAS represents the most severe outcome. Also within this spectrum are partial FAS and alcohol-related birth defects, which are diagnoses that require confirmation of maternal alcohol intake and specific birth defects attributable to alcohol. The term fetal alcohol effects was used previously to describe children with some but not all the features of FAS. Despite considerable knowledge and awareness regarding its teratogenic effects, alcohol continues to be the most common malformation-causing chemical ingested during pregnancy. One of every 29 women who know they are pregnant report alcohol consumption. FASD is considered to be the most common preventable cause of mental retardation. In addition to mental retardation, in utero exposure to alcohol results in increased rates of miscarriage, reduced birth weight, growth retardation, and teratogenic effects including birth defects. The annual cost of FASD according to the 10th Special Report to the US Congress on Alcohol and Health was estimated to be $2.8 billion. The prevalence rates of full FAS case definition in the general US population range from 0.2 to 1.5 cases per 1000 live births annually, which still is a surprisingly small proportion given the number of children exposed to alcohol during fetal development. However, estimates for the entire spectrum range from 3 to 10 times the prevalence of full FAS, resulting in thousands of children born affected by prenatal alcohol each year.
individuals. Further, recent studies using diffusion tensor imaging, magnetic resonance spectroscopy, and functional magnetic resonance imaging have shown that prenatal alcohol disrupts development of both gray and white matter, and results in alterations in cerebral blood flow, neurotransmitters, and neuronal activity even in the absence of structural changes in the brain. Most importantly, this research has revealed that brain function anomalies can exist in individuals even in the absence of tell-tale facial dysmorphology present in children and individuals with FAS. Hence, in addition to the classical features defining FAS, more sensitive tools including behavioral and neurodevelopmental tools are needed to diagnose FASD. Estimating the true incidence of FASD has proved to be a major challenge, especially when a reliable history of alcohol ingestion is absent. Screening for such alcohol exposure information has been aided by a number of brief questionnaires such as the T-ACE, TWEAK, and 10-question AUDIT. More recently, there has been an effort to identify biomarkers that can reflect alcohol exposure, as have been used for tobacco and other drugs of abuse. However, alcohol is mainly metabolized into carbon dioxide and water via oxidative metabolism. Nevertheless, nonoxidative metabolites of alcohol elimination, leading to metabolites such as fatty acid ethyl esters, ethyl glucuronide, and phosphatidyl ethanol, have some potential to reflect alcohol exposure over short periods of time. Newer methodologies, including proteomics and metabolomics, are being leveraged to identify such markers of exposure.
Risk Factors for FASD Several risk factors determine the toxic outcome of in utero alcohol exposure. Risk factors suggested include genetic predisposition, marital status, smoking, use of prescribed or over-the-counter drugs and medications, concomitant usage of other drugs of abuse, occupational or environmental exposure to chemicals, socioeconomic status, and adequate nutrition.
Models of FASD Clinical Assessment of FASD Most experts agree on three diagnostic criteria for the clinical assessment of FASD: (1) prenatal or postnatal growth restriction; (2) central nervous system (CNS) effects, including insufficient development of the brain such as microcephaly, agenesis of corpus callosum; and (3) specific craniofacial dysmorphic features. While earlier studies examining neurodevelopmental changes focused on those individuals most affected by prenatal alcohol, recent studies have examined the range of FASD using novel methodologies. Noninvasive imaging studies have revealed and confirmed structural changes, including reduced brain size and disproportionate reductions in basal ganglia and the cerebellum in affected
590
Research using animal models has shown that each of the major characteristics of human FASD, including craniofacial abnormalities, growth deficiency, and abnormalities of the central nervous system, occurs in one of these animal models: mice, rats, chicks, and primates. Because different species and even strains within species show different degrees of vulnerability to alcohol, experimental results must be interpreted with caution. However, most common animal models of FASD (rats and mice) are very similar to humans and their biochemical processes are virtually the same. Research from animal models has also revealed critical time periods of vulnerability that leads to certain FASD abnormalities. For example, in the mouse and chicken embryos, exposure to alcohol during cranial neural
Encyclopedia of Toxicology, Volume 2
http://dx.doi.org/10.1016/B978-0-12-386454-3.00313-4
Fetal Alcohol Spectrum Disorders crest cells development corresponding to the first 3–4 weeks of human gestation resulted in patterns consistent with observed dysmorphologies of cranial structures and craniofacial defects.
How Much Alcohol Is Safe in Pregnancy? There is no safe drinking level of alcohol during pregnancy. Significant controversy surrounds the amount of alcohol that presents a risk to the fetus and whether a single exposure is of greater consequence than a pattern of exposure during development. Results from clinical and animal studies demonstrate that lower levels of alcohol are needed to produce behavioral anomalies than are needed to produce physical effects and that some brain regions are more susceptible than others. FASD is completely preventable by abstinence to alcohol. The American Academy of Pediatrics recommends counseling women of childbearing age about the effects of alcohol on the fetus. In addition, government-required warning labels about the health effects of alcohol are displayed on alcoholic beverages. A study found almost 80% of 7334 women interviewed were aware of the detrimental effects of alcohol, including the high-risk drinkers. However the warning labels had only a modest effect on personal risk perceptions and drinking behaviors, clearly stressing the need for other effective strategies to decrease alcohol consumption during pregnancy. Considering the cost in economic and human suffering imposed by FASD on the child and the family, prevention via abstinence seems to be the most effective way to reduce the incidence of FASD. Identifying high-risk drinkers is an important first step in this process.
Mechanisms of Induction of FASD The mechanisms leading to FASD remain elusive. A single mechanism for the entire spectrum of FASD is unlikely. However alcohol can (1) trigger cell death in a number of ways, causing different parts of the fetus to develop abnormally; (2) disrupt the way nerve cells develop, travel to form different parts of the brain, and function; (3) constrict the blood vessels resulting in interference with blood flow in and out of the placenta, which can hinder the delivery of nutrients and oxygen to the fetus; and (4) form toxic byproducts after its metabolism (such as acetaldehyde and free radicals), which may become concentrated in the brain and contribute to the development of an FASD. Influences of genetic susceptibility and nutrition may be of critical importance. Clearly, simultaneous or prior exposure to other chemicals may influence the mechanisms and the nature and extent of effects. Several mechanisms involving the direct effects of alcohol on neural development and organogenesis have been explored in animal models. Among them are alcohol-induced changes in neural cell proliferation, reduced growth and neurotropic factors, inhibition of cell adhesion molecule L1, increased oxidative stress and production of free radicals, fetal zinc deficiency, altered vitamin A and folate function, impaired placental function, and disruption of retinoic acid. Of special note is the mechanism of alcohol-induced inhibition of the cell adhesion molecule L1, which is involved in neural cell migration. Recent animal studies have shown that
591
NAPVSIPQ, an active fragment of the glial-derived activitydependent neuroprotective protein that antagonizes the alcohol-induced inhibition of L1, also protects from alcoholinduced fetal growth retardation and demise. These studies open an exciting area of potential pharmacological intervention for FASD; however, the efficacy of any such treatments remains unknown in human subjects.
Interventions for Children with FASD The most desirable approach to prevent FASD is eliminating alcohol consumption during an entire pregnancy. A threelevel model of prevention involving components targeted to the general population, to high-risk communities, and to specific individuals at greatest risk, including women who have already given birth to a child with FASD, has been developed. Of these, targeted prevention efforts have been most promising. Despite prevention efforts, many women continue to consume alcohol during pregnancy, leading to children with FASD. Hence, it is critical to identify interventions that reduce the impact of FASD. The CNS disabilities associated with FASD range from affected individuals presenting combinations of deficits in memory, information processing, academic and social impairments, attention and motor deficits, and executive functioning. Early diagnosis and introduction of interventions in children are associated with decreased long-term adverse outcomes. Recent research has evaluated pharmacological interventions (with stimulant medication), educational and learning strategies, and social communication and behavioral strategies to limit the consequences of FASD. Many of these strategies, including virtual reality training, mathematics intervention, neurocognitive rehabilitation, and parent education and training, have been shown to improve learning, cognitive, and behavioral disabilities in children with FASD.
See also: Alcoholic Beverages and Health Effects; Developmental Toxicology; Mechanisms of Toxicity; Neurotoxicity.
Further Reading Behnke, M., Smith, V.C., Committee on Substance Abuse, Committee on Fetus and Newborn, 2013. Prenatal substance abuse: short- and long-term effects on the exposed fetus. Pediatrics 131 (3), e1009–e1024. Bertrand, J., Interventions for Children with Fetal Alcohol Spectrum Disorders Research Consortium, 2009. Interventions for children with fetal alcohol spectrum disorders (FASDs): overview of findings for five innovative research projects. Res. Dev. Disabil. 30, 986–1006. Brocardo, P.S., Gil-Mohapel, J., Christie, B.R., 2011. The role of oxidative stress in fetal alcohol spectrum disorders. Brain Res. Rev. 67 (1–2), 209–225. Burd, L., Blair, J., Dropps, K., 2012. Prenatal alcohol exposure, blood alcohol concentrations and alcohol elimination rates for the mother, fetus and newborn. J. Perinatol. 32 (9), 652–659. Conover, E.A., Jones, K.L., 2012. Safety concerns regarding binge drinking in pregnancy: a review. Birth Defects Res. A Clin. Mol. Teratol. 94 (8), 570–575. Foltran, F., Gregori, D., Franchin, L., Verduci, E., Giovannini, M., 2011. Effect of alcohol consumption in prenatal life, childhood, and adolescence on child development. Nutr. Rev. 69 (11), 642–659. Frost, E.A., Gist, R.S., Adriano, E., 2011. Drugs, alcohol, pregnancy, and the fetal alcohol syndrome. Int. Anesthesiol. Clin. 49 (1), 119–133.
592
Fetal Alcohol Spectrum Disorders
Fryer, S.L., 2012. Another step forward in relating facial and brain dysmorphologies associated with prenatal alcohol exposure. Alcohol. Clin. Exp. Res. 36 (7), 1131–1133. Grant, T.M., Brown, N.N., Dubovsky, D., Sparrow, J., Ries, R., March–April 2013. The impact of prenatal alcohol exposure on addiction treatment. J. Addict. Med. 7 (2), 87–95. Jones, T.B., Bailey, B.A., Sokol, R.J., 2013. Alcohol use in pregnancy: insights in screening and intervention for the clinician. Clin. Obstet. Gynecol. 56 (1), 114–123. Joya, X., Friguls, B., Ortigosa, S., et al., 2012. Determination of maternal-fetal biomarkers of prenatal exposure to ethanol: a review. J. Pharm. Biomed. Anal. 69, 209–222. Kane, C.J., Phelan, K.D., Drew, P.D., 2012. Neuroimmune mechanisms in fetal alcohol spectrum disorder. Dev. Neurobiol. 72 (10), 1302–1316. Kully-Martens, K., Denys, K., Treit, S., Tamana, S., Rasmussen, C., 2012. A review of social skills deficits in individuals with fetal alcohol spectrum disorders and prenatal alcohol exposure: profiles, mechanisms, and interventions. Alcohol. Clin. Exp. Res. 36 (4), 568–576. Malone, M., Koren, G., 2012. Alcohol-induced behavioural problems in fetal alcohol spectrum disorders versus confounding behavioural problems. J. Popul. Ther. Clin. Pharmacol. 19 (1), e32–e40. Martínez, S.E., Egea, G., 2007. Novel molecular targets for the prevention of fetal alcohol syndrome. Recent Pat CNS Drug Discov. 2 (1), 23–35. Montag, A., Clapp, J.D., Calac, D., Gorman, J., Chambers, C., 2012. A review of evidence-based approaches for reduction of alcohol consumption in Native women who are pregnant or of reproductive age. Am. J. Drug Alcohol Abuse 38 (5), 436–443. Möykkynen, T., Korpi, E.R., 2012. Acute effects of ethanol on glutamate receptors. Basic Clin. Pharmacol. Toxicol. 111 (1), 4–13.
Peadon, E., Rhys-Jones, B., Bower, C., Elliott, E.J., 2009. Systematic review of interventions for children with fetal alcohol spectrum disorders. BMC Pediatr. 9 (35). Pruett, D., Waterman, E.H., Caughey, A.B., 2013. Fetal alcohol exposure: consequences, diagnosis, and treatment. Obstet. Gynecol. Surv. 68 (1), 62–69. Ramadoss, J., Magness, R.R., 2012. Vascular effects of maternal alcohol consumption. Am. J. Physiol. Heart Circ. Physiol. 303 (4), H414–H421. Randall, C.L., 2001. Alcohol and pregnancy: highlights from three decades of research. J. Stud. Alcohol 62, 554–561. Streissguth, A.P., O’Malley, K., 2000. Neuropsychiatric implications and long-term consequences of fetal alcohol spectrum disorders. Semin. Clin. Neuropsychiatry 5, 177–190. Thomas, J.D., Warren, K.R., Hewitt, B.G., 2010. Fetal alcohol spectrum disorders: from research to policy. Alcohol Res. Health 33, 118–126.
Relevant Websites http://www.cdc.gov/ncbddd/fasd/documents/calltoaction.pdf – Centers for Disease Control and Prevention. http://www.mdpi.com/2076-3425/3/2/964/pdf – Indiana University-Purdue University Indianapolis publication. http://www.marchofdimes.com/ – March of Dimes. http://pubs.niaaa.nih.gov/publications/arh25-3/175-184.htm – National Institute on Alcohol Abuse and Alcoholism publication. http://pubs.niaaa.nih.gov/publications/10report/intro.pdf – National Institutes of Health.GOV. http://www.fasdcenter.samhsa.gov/documents/WYNK_Effects_Fetus.pdf – Substance Abuse and Mental Health Services Administration.GOV. http://people.uwec.edu/piercech/fas/fas...htm – University of Wisconsin.