1. Fetal Alcohol Syndrome Fetal alcohol syndrome is among the most commonly known causes of mental retardation and is a major public health problem. What is it, how does it affect people, what can we do about it? These are the issues that will be discussed in this lecture.

2. Historical view of alcohol as a teratogen Foolish, drunken, or harebrain women most often bring forth children like unto themselves Aristotle in Problemata Behold, thou shalt conceive and bear a son: And now, drink no wine or strong drink. Judges 13:7 Rosett, 1984

3. “The offspring of alcoholics have been found defective not because of alcoholism of the parents but because the parents themselves came from a defective stock.” Journal American Medical Association, 132:419, 1946 Ethanol drip was used in obstetrics for threatened premature labor. - Involved I.V. ethanol infusion for 6–10 hours, reaching BAC as high as 160 mg/dl Fuchs, F., et al., Am. J. Obstet. Gynecol., 99:627 (1967) “...the idea of germ poisoning by alcohol in humans may be safely dismissed..” Jellinek, E.M., & Jolliffe, JSA, 1, 1940 Safety of Alcohol and Reproduction in the 20 th Century

5. Fetal Alcohol Syndrome Specific pattern of facial features Pre- and/or postnatal growth deficiency Evidence of central nervous system dysfunction Photo courtesy of Teresa Kellerman

6. FAS – Only the tip of the iceberg Fetal alcohol effects ARND/ARBD Appear normal but clinical suspect Fetal alcohol syndrome Fetal alcohol spectrum disorder(s) Adaped from Streissguth

7. Fetal Alcohol Spectrum Disorders Fetal Alcohol Spectrum Disorder (FASD) is NOT a diagnostic term. Rather, it is an umbrella term used to describe a broad range of effects associated with alcohol use during pregnancy. The spectrum can include physical effects (ARBD) as well as effects on the brain that may result in problems with learning, emotions and behavior (ARND)

8. Improved Diagnostic Schemes

9. Facies in Fetal Alcohol Syndrome Discriminating FeaturesAssociated Features Epicanthal folds Low nasal bridge Minor ear anomalies Micrognathia Short palprebral fissure Indistinct philtrum Thin upper lip In the young child Streissguth, 1994

10. Representative Genetic Syndromes Displaying Some of the Features of FAS Williams syndrome/DeLange Syndrome/VCFS

11. Courtesy of Ann Streissguth Growing up with FAS

12. Incidence of FAS (rates per 1000) Alaska 0.2 non AI/AN 3 AI/AN Aberdeen 2.7 AI/AN BDMP 0.7 Atlanta 0.1 0.3 FAS pFAS IOM 0.5 to 2.0 2 - 8.5 AI/AN Seattle 2.8-3.1 Cleveland 4.6 Roubaix 1.3-4.8 Seattle FASD 9.1 school study 3.1 South Africa Western Cape 4.1 7.4 FAS and PFAS 8.9

13. FAS in Select Populations Can Occur at Higher Rates – Foster Care Astley et al., Application of the fetal alcohol syndrome facial photographic screening tool in a foster care population. J. Pediatr 2002;141:712. www.fasdpn.org/pdfs/foster.pdfwww.fasdpn.org/pdfs/foster.pdf Guides available on www.fasdpn.org Images Copyright Susan Astley, University of Washington Results FAS Prevalence1 per 100 Participation Rate98 % Screened to date2000 Screen for FAS Facial Phenotype using FAS Photographic Analysis Software.  Short palpebral fissure length  Smooth philtrum (Rank 4 or 5)  Thin upper lip (Rank 4 or 5) FAS Palpebral fissure length (PFL)

14. Brain damage resulting from prenatal alcohol photo: Clarren, 1986

15. *** ** CerebrumCerebellum 75 80 85 90 95 100 PEA FAS <p 0.001 p < 0.010 Cerebrum Cerebellum Corpus Callosum Mattson et al., 1994 Change in brain size

16. Corpus callosum abnormalities Mattson, et al., 1994; Mattson & Riley, 1995; Riley et al., 1995

17. Brain Mapping Sowell et al., 2001

18. ADC=Apparent Diffusion Coefficient FA= Fractional Anisotropy CORPUS CALLOSUM Diffusion Tension Image. Midsagittal slice, demonstrating the regions of interest of the genu (CCg) and the splenium (CCs) of corpus callosum. Prenatal Alcohol Exposure and White Matter in the Corpus Callosum of Young Adults Comparison of ADC and FA in corpus callosum of adults with FAS and Controls demonstrating decreased integrity of white matter in alcohol- exposed individuals Genu Splenium (From Ma, et al, 2005, ACER )

19. General Intellectual Performance FSIQVIQPIQ 40 55 70 85 100 115 Standard score IQ scale NC PEA FAS * * * ** * * Mattson, S.N., 1997.

20. Neuropsychological Performance Mattson, et al., 1998

21. 2 1 3 1 2 3 Group 0 2 4 6 Rule Violations NC PEA FAS P<0.001 Move only one piece at a time using one hand and never place a big piece on top of a little piece Starting position Ending position Mattson, et al., 1999 Executive functioning deficits

22. Secondary Disabilities Individuals with FASD have a range of secondary disabilities – disabilities that the individual is not born with, and which could be ameliorated with appropriate interventions. Streissguth, et al., 1996

23. Many studies simply could not be done on humans Confounding factors can rarely be controlled in human studies Alcohol is rarely the only drug used Many abnormalities occur at low rates Epidemiological studies are extremely time consuming and expensive Animal models and prenatal alcohol

24. Animal models – Example of the comparability of effects Growth retardation Facial characteristics Heart, skeletal defects Microcephaly Reductions in basal ganglia and cerebellar volumes Callosal anomalies Hyperactivity, attentional problems Inhibitory deficits Impaired learning Perseveration errors Feeding difficulties Gait anomalies Hearing anomalies Driscoll, et al., 1990; Samson, 1986;

25. Adapted from Sulik & Johnston, 1982 Facial features of FAS in the mouse

26. Alcohol and the Cerebellum Purkinje Cell Layer Pictures courtesy of James West

27. Eyeblink conditioning deficits are correlated with cerebellar damage Adapted from Green et al. 2002

28. Possible mechanisms for alcohol’s effects Impaired progression through cell cycle Impaired glia development - migration, neurotropic factor production, myelination Impaired cell adhesion Alterations in cell membranes Altered production of or responsiveness to factor that regulate growth, cell division, or cell survival Altered regulation of intracellular calcium Increased production of free radicals

29. Courtesy of Michael Charness from Ramanathan et al., 1996

30. Blockade of ethanol’s effects on L1 cell adhesion molecules reduces ethanol’s teratogenic effects Chen et al. 2001

31. Risk Factors Dose of alcohol Pattern of exposure - binge vs chronic Developmental timing of exposure Genetic variation Maternal characteristics Synergistic reactions with other drugs Interaction with nutritional variables

32. Treatment and Prevention Very little research done on these topics Many children with FAS treated for their individual symptoms (e.g. stimulants for ADHD) Animal data indicates that early intervention with environmental variables might have a beneficial effect Warning labels may not be reaching the women most likely to have a child with FAS Intensive, case-management approaches appear to work well. Brief interventions also appear to work

33. Remediation of prenatal alcohol effects Number of slips Klintsova AY., 1998

34. 0 2 4 6 8 ETOHPAIR FEDLAB CHOW GROUP NO INJECTION SALINE ** CHOLINE * * MEAN (± SEM) NUMBER OF CORRECT TRIALS Choline supplementation after prenatal alcohol mitigates learning deficits Adapted from Thomas et al, 2000

35. Prevention – The Birth to 3 Program  Parent-child assistance program  Intensive home visitation model for the highest risk mothers  Paraprofessional Advocates  Paired with client for 3 years following the birth of the target Baby  Link clients with community services  Extensively trained and closely supervised  Maximum caseload of 15  Outcomes  Fewer alcohol/drug affected children  Reduced foster care placement  Reduced dependence on welfare Grant, T.M., 1999; Ernst, C. C., et al. 1999

36. Prevention: Project Care Brief Intervention (BI) for Alcohol Use During Pregnancy in a WIC Setting Compared a brief (10-15 min) intervention (BI) to assessment only (AO) Outcomes Women in BI 5 Xs more likely to stop drinking compared to women in AO Newborn outcomes of birth weight, birth length, and mortality better in BI compared to AO group in heavier drinking women (> 2 drinks/occasion) O’Connor & Whaley, in press 3200 3300 3400 3500 MAX<=2MAX>2 Maximum Drinks Per Drinking Occasion AO BI Estimated marginal means (gms) Birth Weight

37. Intervention: Project Bruin Buddies Parent Assisted Child Friendship Training Compared a Child Friendship Training (CFT) group to a Deferred Treatment Control (DTC) group Parents and children attended 12 - 90 minute sessions over 12 weeks Outcomes Children in the CFT group showed improved social skills and fewer problem behaviors than children in the DTC group Social skills gains were maintained over a 3-month follow up O’Connor, Frankel, Paley et al., in press

38. Summary Fetal Alcohol Spectrum Disorders are developmental disorders that affects children born to women who abuse alcohol during pregnancy. Although FASD are entirely preventable, and in spite of our increasing knowledge about the effects of prenatal alcohol exposure, children continue to be born exposed to high amounts of alcohol. It’s consequences affect the individual, the family, and society. Its costs are tremendous, both personally and financially. Effective treatment and prevention strategies have been developed and new ones must be found and made available.