Advances in Research on Fetal Alcohol Spectrum Disorders
Fetal alcohol spectrum disorders (FASD) are the broad range of neurodevelopmental and physical effects that result from prenatal exposure to alcohol. People with FASD may have facial abnormalities and growth impairments, but the most profound effects are cognitive and behavioral deficits. These deficits can contribute to lifelong learning disabilities, poor social skills, and other problems that impact daily functioning (e.g., living independently or holding a job), as well as overall health and well-being. A significant public health problem, FASD affect an estimated 1 to 5 percent of first-grade children in the United States, according to a 2018 NIAAA-supported study conducted by the Collaboration on Fetal Alcohol Spectrum Disorders Prevalence (CoFASP) and published in the Journal of the American Medical Association.
“Research on FASD is a priority for NIAAA, and for many years we’ve supported studies to understand how alcohol disrupts prenatal development and how FASD can be prevented, diagnosed, and treated,” says NIAAA Director George F. Koob, Ph.D. “Basic, translational, and clinical research are providing valuable insight into the mechanisms that underlie the learning deficits and health problems associated with FASD, thereby shedding light on potential intervention strategies.”
For example, in a recent study led by Wolfram Goessling, M.D., Ph.D., and Olivia Weeks at Harvard Medical School, researchers reported a connection between prenatal alcohol exposure and metabolic disorders in adults. Their analyses of a patient database at a large academic health system found that adults with FASD had an increased incidence of type 2 diabetes, lower HDL (“good”) cholesterol levels, and elevated triglyceride levels compared to those without FASD. Low HDL cholesterol and elevated triglyceride levels are associated with increased risks of stroke and heart attack.
The researchers also investigated the relationships between metabolic dysfunction and prenatal alcohol exposure using a zebrafish model of FASD. When they examined alcohol-exposed zebrafish at adulthood, they found that a high-fat, high-cholesterol diet resulted in obesity and high glucose levels in male but not female zebrafish. High blood glucose is an indicator of diabetes in humans. The researchers also found an association between increased abdominal fat and abnormal liver development in the adult alcohol-exposed zebrafish, suggesting that the molecular mechanism for such alcohol-related pathology is a highly conserved in zebrafish and an evolutionarily basic component of physiology.
Given that alcohol is frequently used with other substances, NIAAA-supported scientists are investigating the combined effects of prenatal exposure to alcohol and substances such as tobacco. As part of the multisite Prenatal Alcohol in SIDS and Stillbirth (PASS) Network, investigators from the United States and South Africa recently reported that children born to mothers who both drank and smoked beyond the first trimester of pregnancy have a twelvefold increased risk for sudden infant death syndrome (SIDS)—the sudden, unexplained death of an infant younger than 1 year—compared to those who were unexposed or only exposed in the first trimester of pregnancy. Dual exposure to alcohol and tobacco was associated with substantially higher risk than exposure to either substance alone, suggesting that combined exposures to alcohol and tobacco have a synergistic effect on SIDS risk.
Kccn2 stands for potassium intermediate/small conductance calcium-activated channel, subfamily N, member 2, and is a gene that encodes a protein channel involved in regulating neuronal excitability in brain systems associated with learning.
In another recent NIAAA-supported study, Kazue Hashimoto-Torii, Ph.D., of the Children’s National Research Institute in Washington, D.C., and colleagues investigated the molecular mechanisms that contribute to the motor deficits associated with prenatal alcohol exposure. Previously, the researchers showed that prenatal alcohol exposure was associated with differences in expression of nearly 100 genes. More recently, they focused on the increased expression of a gene, known as Kcnn2, which encodes a protein involved in regulating neuron activity in brain systems associated with learning (see sidebar for more information) in the motor area of the cerebral cortex in a mouse model of FASD. The researchers demonstrated that increased Kcnn2 expression correlated with deficits in motor skill learning caused by prenatal alcohol exposure. They also observed improvements in these learning deficits when a drug was administered to inhibit activity of Kcnn2, suggesting that Kcnn2 inhibitors may be a potential pharmacological intervention for certain learning disabilities in FASD.
Myelination is the formation of an insulating layer or sheath around neurons that allows electrical impulses to transmit quickly and efficiently.
NIAAA-supported clinical research is also focused on developing interventions to mitigate the adverse effects of prenatal alcohol exposure. Researchers at the University of Minnesota and colleagues have been investigating whether supplementing the diet with choline during early childhood brain development could improve memory and executive function in children with FASD. Choline is an essential nutrient with a key role in myelination (see sidebar) and is known to impact brain development and cognition. In a previous study led by Jeffrey Wozniak, Ph.D., the researchers showed that choline supplementation is feasible and tolerable with minimal side effects among 2- to 5-year-old children who were prenatally exposed to alcohol. In their recently published, 4-year follow-up study on the choline recipients, researchers report that children who received choline had better nonverbal intelligence, visual-spatial skills, and working and verbal memory, as well as fewer symptoms of negative behavior compared to the children who did not receive choline. It is important to note that these effects were evident years after choline administration had ended, suggesting that developmental trajectories had been altered.
“Prenatal alcohol exposure contributes to an array of lifelong physical, cognitive, and behavioral problems,” says Dr. Koob. “These detrimental effects highlight the need for strategies to improve FASD prevention, screening, diagnosis, and treatment. NIAAA’s recent efforts towards the development of a consensus FASD overarching research classification system could accelerate progress in these areas.”
For more information, see “Consensus Meeting on Fetal Alcohol Spectrum Disorders Research Classification” and “Collaborative Initiative on Fetal Alcohol Spectrum Disorders” below.
May, P.A.; Chambers, C.D.; Kalberg, W.O.; Zellner, J.; Feldman, H.; Buckley, D.; Kopald, D.; Hasken, J.M.; Xu, R.; Honerkamp-Smith, G.; Taras, H.; Manning, M.A.; Robinson, L.K.; Adam, M.P.; Abdul-Rahman, O.; Vaux, K.; Jewett, T.; Elliott, A.J.; Kable, J.A.; Akshoomoff, N.; Falk, D.; Arroyo, J.A.; Hereld, D.; Riley, E.P.; Charness, M.E.; Coles, C.D.; Warren, K.R.; Jones, K.L.; and Hoyme, H.E. Prevalence of fetal alcohol spectrum disorders in 4 US communities. JAMA 319(5):474–482, 2018. PMID: 29411031
Weeks, O.; Bossé, G.D.; Oderberg, I.M.; Akle, S.; Houvras, Y.; Wrighton, P.; LaBella, K.; Iversen, I.; Tavakoli, S.; Adatto, I.; Schwartz, A.; Kloosterman, D.; Tsomides, A.; Charness, M.E.; Peterson, R.T.; Steinhauser, M.L.; Fazeli, P.K.; and Goessling, W. Fetal Alcohol Spectrum Disorder Predisposes to Metabolic Abnormalities in Adulthood. Journal of Clinical Investigation 130(5): 2252–2269, 2020. PMID: 32202514
Mohammad, S.; Page, S.J.; Wang, L.; Ishii, S.; Li, P.; Sasaki, T.; Basha, A.; Salzberg, A.; Quezado, Z.; Imamura, F.; Nishi, H.; Isaka, K.; Corbin, J.G.; Liu, J.S.; Imamura Kawasawa, Y.; Torii, M.; and Hashimoto-Torii, K. Kcnn2 Blockade Reverses Learning Deficits in a Mouse Model of Fetal Alcohol Spectrum Disorders. Nature Neuroscience 23(4): 533–543, 2020. PMID: 32203497
Wozniak, J.R.; Fink, B.A.; Fuglestad, A.J.; Eckerle, J.K.; Boys, C.J.; Sandness, K.E.; Radke, J.P.; Miller, N.C.; Lindgren, C.; Brearley, A.M.; Zeisel, S.H.; and Georgieff, M.K. Four-year follow-up of a randomized controlled trial of choline for neurodevelopment in fetal alcohol spectrum disorder. Journal of Neurodevelopmental Disorders 12(1):9, 2020. PMID: 32164522
Elliott, A.J.; Kinney, H.C.; Haynes, R.L.; Dempers, J.D.; Wright, C.; Fifer, W.P.; Angal, J.; Boyd, T.K.; Burd, L.; Burger, E.; Folkerth, R.D.; Groenewald, C.; Hankins, G.; Hereld, D.; Hoffman, H.J.; Holm, I.A.; Myers, M.M.; Nelsen, L.L.; Odendaal, H.J.; Petersen, J.; Randall, B.B.; Roberts, D.J.; Robinson, F.; Schubert, P.; Sens, M.A.; Sullivan, L.M.; Tripp, T.; Van Eerden, P.; Wadee, S.; Willinger, M.; Zaharie, D.; and Dukes, K.A.. Concurrent prenatal drinking and smoking increases risk for SIDS: Safe passage study report. EclinicalMedicine 19:100247. PMID: 32140668
Consensus Meeting on Fetal Alcohol Spectrum Disorders Research Classification
In October 2019, NIAAA held a meeting of international experts to identify essential elements for developing a single research classification system for fetal alcohol spectrum disorders (FASD). Currently, researchers around the world use a variety of classification systems to categorize individuals who are affected by prenatal alcohol exposure. The populations studied by researchers also vary greatly (e.g., clinical vs. research populations). This combination can make comparing research findings difficult and lead to uncertainty in the scientific literature.
The meeting was organized around three features of FASD: neurobehavioral impairment, dysmorphology (changes in physical features), and alcohol exposure. Deliberations of the expert panel helped to sharpen areas of consensus and narrow areas of discrepancy across current research classification systems. The panel also discussed possible framework options for a single, overarching research classification system for FASD. A consensus emerged that any such framework should fully capture the dimensionality of each of the contributing elements—physical, dysmorphology, neurobehavior, and prenatal alcohol exposure—and be adaptable across the lifespan.
Moving forward, meeting participants will test classification elements, thresholds, and frameworks in their own research databases. This process is currently underway, and the results will help experts reach consensus on a single, overarching research classification system whose adoption will harmonize international research efforts. The group plans to inform the research community of their efforts through presentations at upcoming scientific meetings.
Collaborative Initiative on Fetal Alcohol Spectrum Disorders
The Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD), established in 2003, is a research consortium that focuses on improving the diagnosis, prevention, and treatment of fetal alcohol spectrum disorders (FASD). It is composed of a team of multidisciplinary basic, translational, and clinical researchers from across the United States and throughout the world and addresses issues related to prenatal alcohol exposure that occur across the lifespan. Current CIFASD projects focus on brain and physical development, risk and resiliency factors, screening tools and approaches (including telemedicine), biomarker discovery, health effects in youth and adults, and a mobile health intervention. The researchers use novel techniques and approaches to move the field of FASD research forward.
For example, Christie Petrenko, Ph.D., at the University of Rochester’s Mt. Hope Family Center, and Cristiano Tapparello, Ph.D., in the University’s Department of Electrical and Computer Engineering, teamed up to create a mobile phone app for caregivers of children with FASD. The smartphone app, FMF Connect, is designed to give caregivers access to evidence-based content that can help them learn new skills to manage their children’s behavior. It also helps them connect with other caregivers for support and to share ideas. The researchers recently conducted focus group testing with caregivers of children with FASD and reported the findings in the April 2020 issue of JMIR mHealth and uHealth. The participants related how the global themes could address some issues they face, such as limited access to services and feeling isolated. They also offered constructive feedback related to barriers to use and privacy concerns. The researchers are refining the app based on this feedback. After more testing, they plan to evaluate the efficacy of the app in a large-scale randomized controlled trial.
For more information about CIFASD, please visit https://cifasd.org.
Petrenko, C.L.; Parr, J.; Kautz, C.; Tapparello, C; and Olson, H.C. A mobile health intervention for fetal alcohol spectrum disorders (Families Moving Forward Connect): Development and qualitative evaluation of design and functionalities. JMIR mHealth and uHealth 8(4):e14721, 2020. PMID: 32250274