1. Brain Plasticity at Birth Experimental Paradigms for Intervention Studies Gideon Koren MD, FRCPC Motherisk Program Ivey Chair in Mol. Toxicology

2. State of Affairs 2006 Increasing body of experimental evidence: Prenatal ethanol insult can be mitigated by a variety of stimulation paradigms ( Sussman & Koren, JFAS Int 2006 ) Streissguth (Seattle): Repeated evidence that early diagnosis of FAS/ FAE confers protective effects on the children

3. Streissguth (1) ( 2004, J Dev Behav Pediatr 25:228-38) Adolescents with FAS/FAE: 61% disrupted school experience 60% trouble with the law 50% confinement 49% inappropriate sexual behavior 35% alcohol/drug problem

4. Streissguth (2) Odds of escaping these adverse life experiences (x2-4): Early diagnosis of FAS/ FAE Rearing in good stable environment Early age at diagnosis= addressing the needs of the child earlier?

5. How Can We Move Forward? Research Questions: Does enriched environment/ infant stimulation improve neurobehavioral outcome of children with FASD as it appears to do in animals? What method(s) of stimulation would work? How early/ late must these programs start in order to be effective?

6. Methodological Considerations Randomizing children with FASD to “regular” environment vs stimulating paradigm may not be ethical FASD is often diagnosed later in infancy/ toddlers -- should we include all high risk kids? –Drinking mothers? –Babies tested positive for FAEEs?

7. Methodological Approaches (1) Observational– Breaking the Cycle BTC: Measures of Progress 1995-2000 : “…children are developing along a trajectory that is consistent with their age over time.” “…better developmental process than would be expected given the literature on substance-exposed children.” ( Motz et al, 2006)

8. Methodological Approaches (2) Breaking The Cycle: “one stop shop” including: Child development Addiction counseling Social services Home visits Parenting skills Nonjudgmental, warm and empathic environment

9. Methodological Approaches (3) Potential issue in interpreting BTC data: Self selection of mothers to be in program= more motivated mothers=more positive personal attributes for child outcome BTC report : Engaged mothers appeared to be at higher risk for worse outcome than those not successfully engaged( e.g. abuse, psychiatric co-morbidities, giving up children)

10. Methodological Approaches(4) Comparative study of two groups of alcohol- addicted women: 1) BTC-with comprehensive child development program 2) Women receiving addiction treatment but without participation of the children CIHR: Pepler et al, 2005

11. FAEE ’s and Early Diagnosis of FASD ( Hutson, JFAS Int 2006 ) + FAEEs correlate with: Brain weight and body weight in guinea pigs (Brien et al, 2006) Child neurodevelopment (Singer et al, 2003) + Maternal problem drinking Diagnosis of FAS/ FAE (Bearer et al, 2006

12. FAEEs and Early FASD Diagnosis(2) The Grey Bruce Project: Continuing with FAEEs as non- anonymous screening project Positive FAEE cases - to be followed with Social worker Pediatrician Child Psychologist To identify early behavioral problems

13. Antioxidants to mitigate FASD Report on Discontinuation of Study Study recruited problem drinking women Randomized to receive 400IU VitE+1gVit C or Placebo March 2006: Similar regimen for pre-eclampsia (UK): Exposed fetuses= IUGR, no effect on disease; study was D/C Similar study in Toronto was D/C Motherisk (Repro Tox 2005): newborns exposed in utero to mega vit E: 3100g vs 3400g controls Could not be explained by other confounders

14. Cont’d August 2006: Ad Hoc Safety committee recommended to D/C the study