STIRRHS Seminar on Transdisciplinarity

1. STIRRHS Seminar on Transdisciplinarity Dr William D. Fraser MD, MSc, FRCSC June 2nd, 2006

2. Agenda Oxidative Stress INTAPP Trial MIROS Program

3. 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

4. Prevention of preeclampsia?

5. Definition of Oxidative Stress • A disturbance in the prooxidant-antioxidant balance in favor of prooxidants leading to potential damage. Sies, 1991

6. 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•

7. 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

8. Oxidative Stress/ Abnormal Lipid Metabolism / Endothelial Dysfunction /Preeclampsia

9. Antioxidants

10. 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

11. 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

12. INTAPP Protocol review and study design

13. 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)"

14. Population • Stratum I: Nulliparous women without additional identified risk factors • Stratum II: Nulliparous and multiparous women with identified risk factors

15. 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 > 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

16. 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 > 300 mg protein in 24 hours Based on a modification of Canadian Consensus statement definition and ACOG criteria

17. Must include 1 or more of the following selected medical conditions: • Diastolic pressure ≥ 110 mmHg or systolic pressure ≥ 160 mmHg • Proteinuria > 3 g/24h urine collection • Convulsion (eclampsia) • Thrombocytopenia • Elevated liver enzyme levels (AST or ALT >70 U/L) • Creatinine > 180 µmol/L • Hematocrit < 24 and blood transfusion • IUGR <3rd centile • Perinatal death

18. Participant Stratification

19. Treatment Plan

20. INTAPP Schematic design

21. Procedures

22. INTAPP a multidisciplinary team

23. Organisation of sites

24. 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

25. 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)

26. Specimen management system (PIERCE SYSTEM) • Andrew Grant Centre for Research & Evaluation in Diagnostics (CRED) Specimen Management System Université de Sherbrooke

27. Management of blood specimens and vitamin E & C testing

28. 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

29. J.R. Carlson Laboratories inc Timothy Johaneck Robert Meyer • Study medication kit preparation • Shipment to study sites

30. Study sites 42 study sites - Canada 21 - Mexico 10 - China 4 - Argentina 7 Canada Belgium China Mexico Argentina

31. Maternal and Infant Research on Oxidative Stress

32. INTAPP-MIROS Synergy

33. MIROS Synergy among projects

34. MIROS-INTAPP Parallel Structures

35. MIROS Organizational Structure

36. Committees Members

37. CommunicationStrategy

38. Thank you !