Fetal Alcohol Spectrum Disorders
Fetal alcohol spectrum disorders (FASDs) are a group of conditions that can occur in the children of women who consume alcohol during pregnancy.1 FASD refers to a range of disorders, with fetal alcohol syndrome representing the most severe end of the spectrum.
Symptoms of FASD may include:
- Abnormal facial features
- Small head size
- Poor coordination
- Hyperactivity and difficulty paying attention
- Speech/language delays and learning disabilities
- Vision and hearing problems
- Heart, kidney, and bone problems.1,2
There are no standardized criteria or clinical tests to determine whether a child has FASD, making diagnosis difficult.2 There are no specific or highly effective treatments. However, early intervention may improve a child’s development. Treatment often includes medication to manage symptoms (e.g., attention deficits and hyperactivity), behavior and education therapy, and parent training and support.2,3 Because the needs of the affected individual are likely to change as they age, patients with FASD require close monitoring and treatment plans should be adapted as needed.3
The Centers for Disease Control and Prevention estimate FASD frequency ranges from 0.2 to 1.5 cases per 1,000 live births. FASD likely occur three times as frequently as fetal alcohol syndrome.4 As approximately half of all pregnancies in the United States are unplanned, many women who drink alcohol continue to drink during the early weeks of pregnancy because they have not yet realized that they are pregnant.5,6 Importantly, only about 40 percent of women realize that they are pregnant by four weeks of gestation, a critical period for organ development.5
Between 2006 and 2010, 51.5 percent of nonpregnant women reported drinking any alcohol in the past 30 days, and 15 percent reported binge drinking (at least four drinks on one occasion for women). Among pregnant women, 7.6 percent reported consuming any amount of alcohol, and 1.4 percent reported binge drinking.4 According to experts, there is no safe amount of alcohol to consume during pregnancy, and no time during pregnancy when it is safe to drink.1
Prevention and Intervention
Despite Surgeon General’s warnings and educational campaigns targeting women of reproductive age, alcohol-exposed pregnancies continue to occur.7 A new approach to prevention is needed. Many researchers are exploring methods for reaching women of reproductive age in an effort to reduce alcohol consumption.
Developing new tools for reducing alcohol consumption among women of childbearing age is an important area of research. In one such study, women of childbearing age receiving Woman Infant and Children (WIC) services received either personalized feedback or general health information regarding the health effects of alcohol and FASD. More than 70 percent of participants report a reduction in risky drinking behavior.9 A related study, Healthy Choices, compared telephone and in-person brief interventions in women of childbearing age who engaged in risky drinking and did not use effective contraception. A significant overall reduction in alcohol consumption and increase in contraceptive use was reported.10
While interventions for and education of women of childbearing age are necessary for reducing the number of alcohol-exposed pregnancies, physician attitudes toward FASD play an important role as well.8 A 2000 survey revealed that only 33 percent of providers felt prepared to address alcohol use in pregnant patients, and a quarter of respondents felt the medical school training had not adequately prepared them to counsel patients about alcohol use during pregnancy.11 Only half of the providers surveyed counsel all patients about the effects of alcohol use during pregnancy.11
Many health care providers do not agree on acceptable levels of alcohol consumption during pregnancy. While many physicians counsel patients to abstain altogether, others feel “moderate” alcohol consumption during pregnancy is acceptable.8,12,13 A fundamental change in provider attitude is needed, perhaps beginning with ensuring all medical students receive adequate training in counseling patients about alcohol use.
While an ideal approach to eliminating FASD involves preventing alcohol exposed pregnancies in the first place, improved strategies for providing care for affected individuals must also be developed. Numerous studies have suggested that early intervention improves prognosis and quality of life for individuals with FASD, largely by preventing secondary disabilities.1-3,14 Improving diagnostic guidelines and techniques will enable clinicians to make earlier diagnoses and refer patients for intervention services as early as possible.
Biomarkers of maternal alcohol use, detectable in newborns’ meconium, would allow health care providers to identify infants at risk for FASD.2,15 As these children grow, diagnostic follow-ups with physicians would allow for intervention at the earliest sign of disability. Prenatal ultrasound studies seek to determine whether alcohol-exposed fetuses exhibit growth defects that can be detected in utero.
3-D laser facial scans use computer algorithms to detect differences in facial features related to prenatal alcohol exposure that may not be detectable to the naked eye.16,17 Validation of these techniques and determining how best to provide them in a cost-effective and ethical manner, would enhance health care providers’ ability to determine which children and families may need early intervention and support services.
Finally, we must ensure that all families have access to quality intervention services for FASD-affected children. Therapy services can help children learn important skills such as speech and socialization.1 Early diagnosis can also ensure school-age children receive appropriate special education services, tutoring, and support in school.1-3,14 The Family Empowerment Network provides a model for supporting families struggling to find services for children affected by FASD.
This network allows providers to refer families for specific services and also matches families with each other for mentoring and support purposes.14 As stable, nonviolent home environments are extremely important in ensuring the success of a child with FASD, future investment in similar networks can help ensure affected families have access to the multiple support modalities they will require.
Animal Models of Fetal Alcohol Syndrome
A large portion of the FASD research effort is dedicated understanding how alcohol causes damage to the developing fetus, particularly in hopes of developing a therapeutic agent that may reverse or prevent further damage. While the end goal of such research is certainly desirable, there are a number of biological considerations that severely hamper the translational potential of this research.
According to scientists, in order for an animal model to yield results relevant to human FASD, it must meet two criteria. The animal model must exhibit functional or structural disorders similar to those that occur in humans in response to developmental alcohol exposure. The mechanism of action of these disorders must also be similar to those in humans.18 Despite the establishment of these criteria, no single animal model has been developed that exhibits all the diagnostic criteria of FASD as it occurs in humans.19
The simplest animal models of FASD are nonmammalian species such as zebra fish, roundworms, and fruit flies. These species have simple nervous systems and short generation times, and are often used to address basic developmental and genetic questions.19 Chick embryos are also used for their short generation times and ease of access to the developing embryo. However, in all these cases the absence of a placenta connecting mother and developing embryo represent a significant deviation from mammalian development. This is a significant limitation of the systems’ translational relevance to humans. Moreover, some nonmammalian models require large doses of alcohol in order to induce developmental defects, raising concerns about the relevance to the human disorder.19
Both mice and rats are frequently used in FASD studies. The normal physiology and physical and behavioral development has been well-studied in both species.19 Because rats have been so well-characterized in behavioral studies, they are frequently used to study the effect of alcohol exposure on learning and memory.20-22 Mice have been used to study the effect of alcohol exposure on the development of dysmorphic facial features.23,24 Moreover, mice are frequently used by researchers attempting to determine the roles of specific genes in various aspects of FASD.25-27
While transgenic animals are widely used in many fields of research, there are a number of factors that complicate the translational value of data gained from their use. There is no way to control where a transgene is inserted, how many copies are inserted, or how the inserted gene will be translated and processed. The tissue in which a gene is expressed, as well as the timing and abundance of gene expression, all depend on the promoter used.28-30 Finally, inserting or knocking out specific genes may have far-reaching cellular effects that confound interpretation of data.31 It is also important to note that in both mice and rats, the highest velocity of brain growth occurs postnatally, unlike in humans. A rat’s brain is 12 percent of its adult weight at birth, versus 27 percent in man.32 As a result, many FASD studies utilizing rodent models are actually performed with newborn animals—removing both the mother and the placenta from the equation.
Another species that has been studied for decades is the sheep. Because they form a large maternal-fetal unit and are easily implanted with instruments, sheep have long been used to study fetal development and physiology. As a result, this species has extensively utilized to study the effect of alcohol exposure on fetal development.33-35 However, surgical implantation of catheters and other instruments requires anesthesia, which is known to interact with alcohol.19 While sheep have a much longer gestation period than rodents or nonmammalian species, brain development occurs earlier in gestation than it does in humans, and a newborn lamb’s brain is 53 percent of its adult weight at birth.32
Nonhuman primates (NHP) are most closely related to humans and exhibit many similar behaviors, and are frequently been used in biomedical research as a result. Like humans, NHP have long gestation periods.36 Moreover, pregnant NHP can be implanted with catheters for monitoring during experimental procedures.19 As with sheep, however, interactions between anesthetics and alcohol may confound interpretation of results. Moreover, high miscarriage rates have been reported in NHP models of FASD.19 Finally, as with all the other species discussed here, the velocity of brain growth differs between NHP and humans. For example, a rhesus macaque is born with 76 percent of its adult brain weight.32
The National Institute of Alcohol Abuse and Alcoholism, the largest funder of FASD research in the United States, dedicates approximately $30 million annually to fetal alcohol syndrome research.37 Approximately $17 million of this funding was allocated for research involving animal models of FASD in 2013 alone.(http://projectreporter.nih.gov/reporter.cfm) However, more than 4,000 FASD-related publications between 1970 and 2014, only 72 clinical studies involving FASD were published. Only two of these studies tested a novel therapeutic for affected children. Such a small return on an enormous investment of time and financial resources casts doubt on the ability of these models yield results that can be effectively translated into treatments for FASD-affected individuals.
There are a number of ethical issues intrinsic to the use of animals in research, beginning with the conditions in which animals are housed. Laboratory and experimental conditions are inherently stressful. For example, rodents that have been handled by laboratory personnel exhibit increased heart rate, body temperature, and circulating levels of stress-related hormones such as cortisol. Rats and mice exhibit stress-related behaviors such as excessive grooming and aggression, and may develop stress-related gut inflammation.38-42 Blood collection from rodents, rabbits, dogs, and NHP results in increased cortisol and blood glucose levels.38,43-46 These changes in basal stress responses persist for hours or days following handling.38
Large animals used in FASD research are frequently subjected to multiple surgeries, long-term instrumentation, and frequent sample collections. Sample collection from NHP commonly results in overt fear responses, such as vocalizations and physical resistance.19,38,47 A 2005 review of animal models of FASD cited restraint stress in NHP as a confounding issue when interpreting data collected from these models.19 Simply witnessing the effects of these procedures may influence the basal stress responses of neighboring animals.48-50 Overall, these studies confirm that laboratory housing conditions and the procedures performed on animals not only cause significant fear and stress on the subjects and other animals nearby, but likely change the basic physiology of the animals, rendering results from animal models highly unrelated to human biology.
Specific to the ethics of FASD- and other alcohol-related animal models is the issue of alcohol consumption. Alcohol abuse is a uniquely human condition—no other species willingly consumes alcohol. Animals used in alcohol-related experiments are sometimes trained to drink sweetened alcohol, but are frequently injected or gavaged with extremely high doses of ethanol.51-54 Oral gavage itself has been shown to cause changes in body temperature, hormone levels, and liver function in mice and rats.55-57 Consumption of alcohol in rats has been linked to changes in the hypothalamic-pituitary-adrenal (HPA) axis, which plays a central role in stress responses.53,54
HPA axis activation and increased corticosteroid production has been reported in NHP following ethanol administration as well.58 Researchers are studying the effects of alcohol consumption in species that metabolize ethanol differently, receive ethanol via a different route, and exhibit stress responses due to housing conditions, frequently handling, and alcohol consumption itself.59 These models are both unethical and remarkably far removed from alcohol abuse as it occurs in humans.
Perhaps not surprisingly, a search of clinical FASD literature dating back to 1999 reveals most publications are related to prevention, diagnostics, and intervention. If the basic science models aren’t working, and no new treatments are being developed, the use of animals in highly invasive research is all the more unethical and cause for concern.
The Future of FASD Research
FASD remains the leading cause of preventable birth defects and developmental disorders in the United States. NIAAA provides approximately $30 million annually to FASD-related research.37 More than half of this funding is dedicated to basic science research in animal models of FASD. Despite these investments, rates of maternal drinking remain relatively consistent, and no novel therapies have been identified. A new approach is needed. Rather than continuing to funnel precious research funding into animal-related studies with limited translational capacity, NIAAA and other funding bodies ought to invest in research aimed at discovering novel methods for educating women about the effects of fetal alcohol exposure, new diagnostic and treatment paradigms, family support networks, and developing methods for widespread instillation of these practices.
Moreover, medical schools should be required to train students to counsel patients about the effects of alcohol abuse and educating practicing physicians through CME requirements about the importance of and methods for screening patients for alcohol abuse issues will allow providers to recognize patients at risk for alcohol exposed pregnancies. These strategies will increase the likelihood of physicians referring at-risk patients for the care required to prevent alcohol exposed pregnancies. Ultimately, only by refocusing our research and education strategies on the human patients affected by FASD, rather than the distraction of animal models of the disorders, will we successfully prevent alcohol exposed pregnancies and provide adequate care for those already impacted by them.
- Facts about FASDs. 2014 May 24, 2014; Available from: http://www.cdc.gov/ncbddd/fasd/facts.html.
- Paintner A, Williams AD, Burd L. Fetal alcohol spectrum disorders--implications for child neurology, part 2: diagnosis and management. J Child Neurol. 2012;27:355-362.
- Pruett D, Waterman EH, Caughey AB. Fetal alcohol exposure: consequences, diagnosis, and treatment. Obstet Gynecol Surv. 2013;68:62-69.
- Data & Statistics. 2014 May 23, 2014; Available from: http://www.cdc.gov/ncbddd/fasd/data.html.
- Floyd RL, Decoufle P, Hungerford DW. Alcohol use prior to pregnancy recognition. Am J Prev Med. 1999;17:101-107.
- Finer LB, Henshaw SK. Disparities in rates of unintended pregnancy in the United States, 1994 and 2001. Perspect Sex Reprod Health. 2006;38:90-96.
- Warren KR, Hewitt BG, Thomas JD. Fetal alcohol spectrum disorders: research challenges and opportunities. Alcohol Res Health. 2011;34:4-14.
- Waterman EH. Pruett D, Caughey AB. Reducing fetal alcohol exposure in the United States. Obstet Gynecol Surv. 2013;68:367-378.
- Delrahim-Howlett K, Chambers CD, Clapp JD, et al. Web-based assessment and brief intervention for alcohol use in women of childbearing potential: a report of the primary findings. Alcohol Clin Exp Res. 2011;35:1331-1338.
- Wilton G, Moberg DP, Van Stelle KR, Dold LL, Obmascher K, Goodrich J. A randomized trial comparing telephone versus in-person brief intervention to reduce the risk of an alcohol-exposed pregnancy. J Subst Abuse Treat. 2013;45:389-394.
- Diekman ST, Floyd RL, Découflé P, Schulkin J, Ebrahim SH, Sokol RJ. A survey of obstetrician-gynecologists on their patients' alcohol use during pregnancy. Obstet Gynecol. 2000;95:756-763.
- Nevin AC, Parshuram C, Nulman I, Koren G, Einarson A. A survey of physicians knowledge regarding awareness of maternal alcohol use and the diagnosis of FAS. BMC Fam Pract. 2002;3:2.
- Tough SC, Ediger K, Hicks M, Clarke M. Rural-urban differences in provider practice related to preconception counselling and fetal alcohol spectrum disorders. Can J Rural Med. 2008;13:180-188.
- Wilton G, Plane MB. The Family Empowerment Network: a service model to address the needs of children and families affected by Fetal Alcohol Spectrum Disorders. Pediatr Nurs. 2006;32:299-306.
- Memo L, Gnoato E, Caminiti S, Pichini S, Tarani L. Fetal alcohol spectrum disorders and fetal alcohol syndrome: the state of the art and new diagnostic tools. Early Hum Dev. 2013(suppl 1):S40-S43.
- Fang S, McLaughlin J, Fang J, et al, and the Collaborative Initiative on Fetal Alcohol Spectrum Disorders. Automated diagnosis of fetal alcohol syndrome using 3D facial image analysis. Orthod Craniofac Res. 2008;11:162-171.
- Mutsvangwa TE, Smit J, Hoyme HE, et al. Design, construction, and testing of a stereo-photogrammetric tool for the diagnosis of fetal alcohol syndrome in infants. IEEE Trans Med Imaging. 2009;28:1448-1458.
- Wilson SE, Cudd TA. Focus on: the use of animal models for the study of fetal alcohol spectrum disorders. Alcohol Res Health. 2011;34:92-98.
- Cudd TA. Animal model systems for the study of alcohol teratology. Exp Biol Med (Maywood). 2005;230:389-393.
- Murawski NJ, Jablonski SA, Brown KL, Stanton ME. Effects of neonatal alcohol dose and exposure window on long delay and trace eyeblink conditioning in juvenile rats. Behav Brain Res. 2013;236:307-318.
- Brown KL, Calizo LH, Goodlett CR, Stanton ME. Neonatal alcohol exposure impairs acquisition of eyeblink conditioned responses during discrimination learning and reversal in weanling rats. Dev Psychobiol. 2007;49:243-257
- Green JT. The effects of ethanol on the developing cerebellum and eyeblink classical conditioning. Cerebellum. 2004;3:178-187.
- Sulik KK. Genesis of alcohol-induced craniofacial dysmorphism. Exp Biol Med (Maywood). 2005;230:366-375.
- Shen L, Ai H, Liang Y, et al. Effect of prenatal alcohol exposure on bony craniofacial development: a mouse MicroCT study. Alcohol. 2013;47:405-415.
- Kaminen-Ahola N, Ahola A, Flatscher-Bader T, et al. Postnatal growth restriction and gene expression changes in a mouse model of fetal alcohol syndrome. Birth Defects Res A Clin Mol Teratol. 2010;88:818-826.
- Dong J, Sulik KK, Chen SY. Nrf2-mediated transcriptional induction of antioxidant response in mouse embryos exposed to ethanol in vivo: implications for the prevention of fetal alcohol spectrum disorders. Antioxid Redox Signal. 2008;10:2023-2033.
- Kleiber ML, Diehl EJ, Laufer BI, et al. Long-term genomic and epigenomic dysregulation as a consequence of prenatal alcohol exposure: a model for fetal alcohol spectrum disorders. Front Genet. 2014;5:161.
- Davis J, Maillet M, Miano JM, Molkentin JD. Lost in transgenesis: a user's guide for genetically manipulating the mouse in cardiac research. Circ Res. 2012;111:761-777.
- Geghman K, Li C. Practical considerations of genetic rodent models for neurodegenerative diseases. Methods Mol Biol. 2011;793:185-193.
- Toman PD, Pieper F, Sakai N, et al. Production of recombinant human type I procollagen homotrimer in the mammary gland of transgenic mice. Transgenic Res. 1999;8:415-427.
- Thyagarajan T, Totey S, Danton MJ, Kulkarni AB. Genetically altered mouse models: the good, the bad, and the ugly. Crit Rev Oral Biol Med. 2003;14:154-174.
- Dobbing J, Sands J. Comparative aspects of the brain growth spurt. Early Hum Dev. 1979;3:79-83.
- Brien JF, Clarke DW, Richardson B, Patrick J. Disposition of ethanol in maternal blood, fetal blood, and amniotic fluid of third-trimester pregnant ewes. Am J Obstet Gynecol. 1985;152:583-590.
- Gleason CA, Hotchkiss KJ. Cerebral responses to acute maternal alcohol intoxication in immature fetal sheep. Pediatr Res. 1992;31:645-648.
- Cudd TA, Chen WJ, West JR. Fetal and maternal thyroid hormone responses to ethanol exposure during the third trimester equivalent of gestation in sheep. Alcohol Clin Exp Res. 2002;26:53-58.
- Schneider ML, Moore CF, Kraemer GW, Roberts AD, DeJesus OT. The impact of prenatal stress, fetal alcohol exposure, or both on development: perspectives from a primate model. Psychoneuroendocrinology. 2002;27:285-298.
- NIAAA. Fetal Alcohol Spectrum Disorders. 2014 [cited 2014 July 21]; Available from: http://niaaa.nih.gov/research/major-initiatives/fetal-alcohol-spectrum-disorders.
- Balcombe JP, Barnard ND, Sandusky C. Laboratory routines cause animal stress. Contemp Top Lab Anim Sci. 2004;43:42-51.
- Black RW, Fowler RL, Kimbrell G. Adaptation and habituation of heart rate to handling in the rat. J Comp Physiol Psychol. 1964;57:422-425.
- Duke JL, Zammit TG, Lawson DM. The effects of routine cage-changing on cardiovascular and behavioral parameters in male Sprague-Dawley rats. Contemp Top Lab Anim Sci. 2001;40:17-20.
- Sharp JL, Zammit TG, Azar TA, Lawson DM. Stress-like responses to common procedures in male rats housed alone or with other rats. Contemp Top Lab Anim Sci. 2002;41:8-14.
- Sharp JL, Zammit TG, Lawson DM. Stress-like responses to common procedures in rats: effect of the estrous cycle. Contemp Top Lab Anim Sci. 2002;41:15-22.
- Knudtzon J. Plasma levels of glucagon, insulin, glucose and free fatty acids in rabbits during laboratory handling procedures. Z Versuchstierkd. 1984;26:123-133.
- Haemisch A, Guerra G, Furkert J. Adaptation of corticosterone-but not beta-endorphin-secretion to repeated blood sampling in rats. Lab Anim. 1999;33:185-191.
- Reinhardt V, Cowley D, Scheffler J, Vertein R, Wegner F. Cortisol response of female rhesus monkeys to venipuncture in homecage versus venipuncture in restraint apparatus. J Med Primatol. 1990;19:601-606.
- Slaughter MR, Birmingham JM, Patel B, et al. Extended acclimatization is required to eliminate stress effects of periodic blood-sampling procedures on vasoactive hormones and blood volume in beagle dogs. Lab Anim. 2002;36:403-410.
- Reinhardt V. Working with rather than against macaques during blood collection. J Appl Anim Welf Sci. 2003;6:189-197.
- Sharp J, Zammit T, Azar T, Lawson D. Are "by-stander" female Sprague-Dawley rats affected by experimental procedures? Contemp Top Lab Anim Sci. 2003;42:19-27.
- Bickhardt, K., et al., Influence of bleeding procedure and some environmental conditions on stress-dependent blood constituents of laboratory rats. Lab Anim. 1983;17:161-165.
- Flow BL, Jaques JT. Effect of room arrangement and blood sample collection sequence on serum thyroid hormone and cortisol concentrations in cynomolgus macaques (macaca fascicularis). Contemp Top Lab Anim Sci. 1997;36:65-68.
- Aston R, Stolman S. Influence of route and concentration of ethanol upon central depressant effect in the mouse. Proc Soc Exp Biol Med. 1966;123:496-498.
- Spirduso WW, Mayfield D, Grant M, Schallert T. Effects of route of administration of ethanol on high-speed reaction time in young and old rats. Psychopharmacology (Berl). 1989;97:413-417.
- Silva SM, Madeira MD, Ruela C, Paula-Barbosa MM. Prolonged alcohol intake leads to irreversible loss of vasopressin and oxytocin neurons in the paraventricular nucleus of the hypothalamus. Brain Res. 2002;925:76-88.
- Silva SM, Santos-Marques MJ, Madeira MD. Sexually dimorphic response of the hypothalamo-pituitary-adrenal axis to chronic alcohol consumption and withdrawal. Brain Res. 2009;1303:61-73.
- Brown AP, Dinger N, Levine BS. Stress produced by gavage administration in the rat. Contemp Top Lab Anim Sci. 2000;39:17-21.
- Roberts RA, Soames AR, James NH, Gill JH, Wheeldon EB. Dosing-induced stress causes hepatocyte apoptosis in rats primed by the rodent nongenotoxic hepatocarcinogen cyproterone acetate. Toxicol Appl Pharmacol. 1995;135:192-199.
- Germann PG, Ockert D. Granulomatous inflammation of the oropharyngeal cavity as a possible cause for unexpected high mortality in a Fischer 344 rat carcinogenicity study. Lab Anim Sci. 1994;44:338-343.
- Porcu P, Grant KA, Green HL, Rogers LS, Morrow AL. Hypothalamic-pituitary-adrenal axis and ethanol modulation of deoxycorticosterone levels in cynomolgus monkeys. Psychopharmacology (Berl). 2006;186:293-301.
- Zorzano A, Herrera E. In vivo ethanol elimination in man, monkey and rat: a lack of relationship between the ethanol metabolism and the hepatic activities of alcohol and aldehyde dehydrogenases. Life Sci. 1990;46:223-230.