STIRRHS Seminar on Transdisciplinarity

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STIRRHS Seminar on Transdisciplinarity

• Dr William D. Fraser MD, MSc, FRCSC
• June 2nd, 2006

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Agenda

• Oxidative Stress
• INTAPP Trial
• MIROS Program

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Hypertension and pregnancy

• Gestational hypertension
• Majority high-risk antenatal visits high BP
• (24 of antenatal hospital admissions)
• Ranked first among the direct obstetric causes of
  maternal death
• Perinatal deaths (preterm delivery intrauterine
  growth restriction)
• 10 to 25 of all very low birth weight infants
• Preeclampsia, or proteinuric gestational
  hypertension
• Accounts for 1/3 of maternal deaths in pregnancy
• Eclampsia
• 20 occur without antecedent proteinuria

Delivery is the only known cure of Preeclampsia
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Prevention of preeclampsia?
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Definition of Oxidative Stress

• A disturbance in the prooxidant-antioxidant
  balance in favor of prooxidants leading to
  potential damage.

Sies, 1991
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Oxidative Stress Reactive Oxygen and Nitrogen
Species
Reactive nitrogen species Nitric oxide,
NO Nitrogen dioxide, NO2
Reactive oxygen species Superoxide,
O2- Hydroxyl, OH Peroxyl, RO2 Alkoxyl,
RO Hydroperoxyl, HO2
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Antioxidants of Interest

• Carotenoids
• Xanthophylls
• Metallothionein
• Coenzyme Q10
• Uric acid
• Flavonoids Polyphenols
• Herbal remedies such as theaflavin, Ginko biloba,
  etc.

• Vitamin E (Tocopherol)
• Vitamin C (Ascorbic Acid)
• Vitamin A
• Proteins
• Superoxide dismutase
• Glutathione peroxidase
• Catalase
• Ceruloplasmin
• Beta-carotene

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Oxidative Stress/ Abnormal Lipid Metabolism /
Endothelial Dysfunction /Preeclampsia
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Antioxidants
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Antioxidants in the Prevention of Preeclampsia

• Primary Outcome Measure
• Mean PAI-1/PAI-2 during gestation in
  completed-study cohort

0.50 0.45 0.40 0.35 0.30 0.25 0.20
Placebo (n 82) Vitamins (n 79)
12 16 20 24 28 32 36 40
Chappell et coll., Lancet, 1999
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Secondary Outcome Measure Frequency of
Preeclampsia
1512 Women Screened by uterine Doppler 284
Randomised Women with High Risk of Preeclampsia
142 Placebo Total Preeclampsia 24 (17)
141 Vit C E Total Preeclampsia 11 (8)
Relative Risk 0.39 95 CI 0.17-0.90
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INTAPP Protocol review and study design
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Primary Hypotheses

• Oral antenatal supplementation with vitamins C
  and E reduces the incidence of "Gestational
  hypertension (with or without proteinuria) and
  its adverse condition(s)"

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Population

• Stratum I Nulliparous women without additional
  identified risk factors
• Stratum II Nulliparous and multiparous women
  with identified risk factors

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Inclusion criteria

• Women between 120/7 and 186/7 weeks of pregnancy
• Gestational age of patients will be based on the
  last menstrual period and confirmed by early
  ultrasound examination. (if discrepancy gt 7 days,
  use ultrasound to estimate gestational age)
• At least 18 years old
• Speak a language known by the medical staff
• Plan to deliver in a participating centre

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Definition of the Primary Outcome
Gestational hypertension (with or without
proteinuria) and its adverse condition(s)

• Gestational hypertension
• Two or more readings of diastolic blood pressure
  ? 90 mmHg taken 4 hours apart within a 24-hour
  period and occurring after 20 weeks of pregnancy
• Severe gestational hypertension
• Two recordings of diastolic blood pressure of
  ?110 mmHg or systolic pressure ?160 mmHg at least
  4 hours apart within a 24 hour period
• Proteinuria
• Excretion of gt 300 mg protein in 24 hours

Based on a modification of Canadian Consensus
statement definition and ACOG criteria
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Must include 1 or more of the following selected
medical conditions

• Diastolic pressure 110 mmHg or systolic
  pressure 160 mmHg
• Proteinuria gt 3 g/24h urine collection
• Convulsion (eclampsia)
• Thrombocytopenia
• Elevated liver enzyme levels (AST or ALT gt70 U/L)
  
• Creatinine gt 180 µmol/L
• Hematocrit lt 24 and blood transfusion
• IUGR lt3rd centile
• Perinatal death

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Participant Stratification
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Treatment Plan
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INTAPP Schematic design
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Procedures
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INTAPP a multidisciplinary team
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Organisation of sites
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Central Laboratory

• Aim of this procedure
• Ensure appropriate processing, storing and
  shipping of blood samples in order to be able to
  perform sensitive analyses of vitamin C E
• Ensure an efficient system of communication
  between study sites, CL, GEREQ and the Center for
  Research and Evaluation in Diagnostics.
• Testing of Vitamins C E
• Biological Specimen Bank

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Central Laboratory

• At reception of your samples, CL will make an
  inventory of the samples, using a bar code
  scanner to ensure that content match the
  Inventory log
• This will automatically creates a record in the
  MGS system at CL.
• MGS will then store the following information
• Date and time of reception
• Volume of samples
• Quality of samples (intact and frozen)

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Specimen management system (PIERCE SYSTEM)

• Andrew Grant
• Centre for Research Evaluation
• in Diagnostics (CRED)
• Specimen Management System
• Université de Sherbrooke

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Management of blood specimens and vitamin E C
testing
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Food Frequency Questionnaire (FFQ)

• Canada
• Bryna Shatenstein, PhD
• Montreal Geriatric Institute
• Mexico
• Maria-Soccoro Parra, PhD
• National Institute of Public Health
• China
• Baoquing Mo, PhD
• Nanjing Medical University

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J.R. Carlson Laboratories inc

• Timothy Johaneck
• Robert Meyer
• Study medication kit preparation
• Shipment to study sites

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Study sites

• 42 study sites
• - Canada 21 - Mexico 10
• - China 4 - Argentina 7

Canada
Belgium
China
Mexico
Argentina
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• Maternal and Infant Research
• on Oxidative Stress

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INTAPP-MIROS Synergy
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MIROS Synergy among projects
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MIROS-INTAPP Parallel Structures
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MIROS Organizational Structure
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Committees Members
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Communication Strategy
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Thank you !