Transcript Introduction

Evaluating the Effectiveness
of Antioxidant Treatment in
Pregnant Alcohol Exposed
Mothers
Y. Ingrid Goh HBSc, Gideon Koren MD
Introduction
• Fetal alcohol syndrome (FAS) and alcoholrelated 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
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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 randomizedcontrolled 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
GROUP B
•Vitamin C
•Vitamin E
•Multivitamin
•Counseling
•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 Results
2284 callers to Motherisk Alcohol and
Substance Line
105 callers with TWEAK3
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
2 women
reported
miscarriage
1 woman
pregnant
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