Evaluating the Effectiveness of Antioxidant Treatment in Pregnant Alcohol Exposed

Mothers

Y. Ingrid Goh HBSc, Gideon Koren MD

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)

FASD• Cranial facial dysmorphology• Pre/postnatal growth deficiency• Neurobehavioural impairments

Secondary Comorbidities

• Mental health problems• Poor achievement in school• Disruptive school experience• Dependent living• Employment problems• Poor socio-economics• Substance abuse• Legal problems

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

EViCE Study

Effectiveness of Vitamin C and E in alcohol-exposed pregnancies

EViCE

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

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

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

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

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

EViCE Study Design

GROUP A

•Vitamin C•Vitamin E•Multivitamin•Counseling

GROUP B

•Placebo•Placebo•Multivitamin•Counseling

GROUP C

•Counseling

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

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

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

Recruitment Results2284 callers to Motherisk Alcohol and

Substance Line

105 callers with TWEAK3

71 women lived within study area

66 eligible to participate

More Recruitment Results

66 eligible callers

6 women randomized into study

3 women gave birth

1 woman pregnant

2 women reported

miscarriage

Patient Attrition

Number of Callers Reason

28 Lost to follow-up

10 No show for appointment

5 Therapeutic abortion

3 Refused to participate

3 No contact number provided

2 Refused to take study drug

2 “Lives too far”

2 “Too many appointments”

2 Refused referral

2 Miscarried

1 Doctor dismissed as “low risk pregnancy”

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

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