1. Evaluating the Effectiveness of Antioxidant Treatment in Pregnant Alcohol Exposed Mothers Y. Ingrid Goh HBSc, Gideon Koren MD

2. Introduction Fetal alcohol syndrome (FAS) and alcohol- related neurodevelopmental disorder (ARND) are the most preventable birth defects among children FASD affects 1 of 100 live births »(May et al. 2001) Estimated $1 million cost of caring for a person with FASD »(Stade et al. 2001)

3. FASD Cranial facial dysmorphology Pre/postnatal growth deficiency Neurobehavioural impairments

4. Secondary Comorbidities Mental health problems Poor achievement in school Disruptive school experience Dependent living Employment problems Poor socio-economics Substance abuse Legal problems

5. Background Ethanol metabolism results in the production of oxidative stress which can result in the selective loss of neurons and depressed neurogenesis in the developing fetus »Olney 2004 Systematic review of experimental antioxidant therapy in animal studies suggested that different combinations of antioxidants can attenuate damaging effects of ethanol on offspring »Cohen-Kerem et al. 2003

6. EViCE Study Effectiveness of Vitamin C and E in alcohol-exposed pregnancies EViCE

7. Safety of Antioxidants Vitamin C –Water-soluble, excess amounts excreted –Not associated with teratogenicity Vitamin E –Safe when taken in 2nd and 3rd trimesters of pregnancy –Motherisk study of 58 women ingesting >400 I.U. vitamin E daily in the first trimester of their pregnancy noted no major congenital malformations –Animal study reported vitamin E prevent congenital malformations in offspring of diabetic rats resulted in a decreased rate of malformation

8. Objective Compare the effectiveness of high doses of vitamin C (1g) and vitamin E (400IU) in combination with folic acid (0.8mg) in mitigating adverse effect with regular prenatal vitamin supplementation

9. Hypothesis High dose daily combination of vitamin C (1g), vitamin E (400IU) and folate (0.8mg) will be more efficacious than regular dosages of prenatal vitamins in attenuating the neurobehavioral and other adverse fetal effects of ethanol

10. Methods Participants –Pregnant women calling Motherisk Alcohol and Substance Helpline regarding alcohol exposure Invited to participate in a randomized- controlled trial (EViCE study) based on inclusion and exclusion criterion

11. Inclusion 0-24 weeks pregnant Women with significant alcohol exposure in pregnancy: –TWEAK≥3 (screens for high-risk drinkers); –Chronic drinkers; or –Heavy binge drinkers Exclusion Pregnancy≥25 weeks pregnant Prior participation in other study ≤30 days Participating in another trial

12. EViCE Study Design GROUP A Vitamin C Vitamin E Multivitamin Counseling GROUP B Placebo Multivitamin Counseling GROUP C Counseling

13. EViCE Study Methodology Participant meets with study coordinator and doctor every 2 months during pregnancy for assessment Participant contacted by phone between visits Blood and urine collected Questionnaires completed Study drug issued

14. EViCE Study Methodology Meconium and hair collection at delivery Baby assessed at 3, 6, and 14 months for achievements of developmental milestones Optional annual follow-up of baby at Hospital for Sick Children’s FAS Clinic

15. EViCE Study Methodology Study population of 189 women total needed to detect medium effect size of 8 points IQ with power 80% and alpha=0.05 Analysis by ANCOVA Primary endpoint: IQ as measured by Mullen scales

16. Recruitment Results 2284 callers to Motherisk Alcohol and Substance Line 105 callers with TWEAK3 71 women lived within study area 66 eligible to participate

17. More Recruitment Results 66 eligible callers 6 women randomized into study 3 women gave birth 1 woman pregnant 2 women reported miscarriage

18. Patient Attrition Number of CallersReason 28Lost to follow-up 10No show for appointment 5Therapeutic abortion 3Refused to participate 3No contact number provided 2Refused to take study drug 2“Lives too far” 2“Too many appointments” 2Refused referral 2Miscarried 1Doctor dismissed as “low risk pregnancy”

19. Conclusions & Implications Recruitment of alcohol-exposed pregnant women into a randomized control trial is difficult Lessons in recruitment of high-risk population: –Essential to immediately engage with subjects –Closer working relations with healthcare providers required –Improved success with multi-centre trial

20. Acknowledgements Sponsored by CIHR FAS-NET Grant Supported by Pharmavite, The Apotex Group, Bell Mobility & RU Communicating Marina Avner MD, Alon Shrim MD, Massoud Rezvani MD, Joanne Rovet PhD, Wendy Ungar PhD Members of the Motherisk Program