Update on Prediction & prevention of Preeclampsia

1. Prof. Aboubakr Elnashar Benha University Hospital, Egypt Update on Prediction & prevention of Preeclampsia

2. Prediction: • Routine urine analysis • Prevention: • Chocolate

3. Outline • Introduction • Prediction • Prevention

4. Cochrane Systematic Review Gold Standard' for high-quality systematic reviews

5. Preeclampsia: • Hypertension associated with proteinuria.

6. Pathogenesis: • unknown (Barton& Sibai, 2008). • Impaired trophoblast differentiation& invasion • Placental & endothelial dysfunction • Immune maladaptation to paternal Ags • Exaggerated systemic inflam response.

7. Pathogenesis: • Differs with various risk factors: • PG Vs MG with previous PE • preexisting vas dis • preexisting DM or • multifetal gestation.

8. In PE: Impaired trophoblast differentiation & invasion

9. Placental and endothelial dysfunction

10. PREDICTION OF PE • Why prediction is important? • The ideal screening test • Methods I. Preconception factors II. Pregnancy-Related Factors 1. Risk factors 2. Markers

11. Why prediction is important: • The risk for recurrent PE can be as high as 65%(Barton& Sibai, 2008). • PE is associated with substantial maternal& perinatal complications

12. The ideal Screening test: Simple Noninvasive Rapid Inexpensive Easy to perform early in pregnancy Highly sensitivity & predictive.

13. I. Preconception factors 1st step in the management of a woman with a history of PE is to conduct a detailed evaluation of potential risk factors(Barton& Sibai, 2008).

14. Preconceptional Risk Factors Rates of preeclampsia depend on: severity of underlying complications& combinations of risk factors.

15. II. Pregnancy-Related Factors • Regular antenatal care is mandatory for the prevention & early detection of PE. • Risk factors:Magnitude of risk depends on the number of factors • Hydrops/hydropic degeneration of the placenta • Multifetal gestation • Unexplained FGR • Gestational hypertension • UTI • Periodontal infection • Markers • Biophysical • Biochemical

16. Markers • Many • Based on: pathophysiological abnormalities

17. SCREENING TESTS FOR PE (WHO, 2004) • I. Placental perfusion & vascular resistance dysfunction • Mean arterial blood pressure • Roll over test • Doppler ultrasound • Isometric exercise test • Intravenous infusion of angiotensin II • Platelet angiotensin II binding • Platelet calcium response to arginine vasopressin • Renin • 24-hour ambulatory blood pressure monitoring • II. Fetoplacental unit dysfunction • Human chorionic gonadotropin • Alpha fetoprotein • Estriol • Inhibin A • Pregnancy-associated plasma protein A • Activin A • Corticotropin release hormone

18. III. Renal dysfunction Serum uric acid Microalbuminuria Urinary calcium excretion Urinary kallikrein Microtransferrinuria N-acetyl- glucosarninidase IV. Endothelial& oxidant stress dysfunction Platelet count Platelet activation and endothelial cell adhesion molecules Prostacyclin Cytokines Isoprostanes, Antiphospholipid antibodies, Placenta growth factor Hematocrit Antithrombin Ill Calcium Transferrin Atrial natriuretic peptide Fibronectin Endothelin Thromboxane Homocysteine Serum lipids Insulin resistance Plasminogen activator inhibitor Leptin Total proteins Magnesium Ferritin Haptoglobin microglobulin Genetic markers

19. I. Biophysical • Mean arterial pressure • (2D BP+S BP)/3 • Better predictor of PE than S& D BP(BMJ 200817;336:111; Meta-analysis of 34 RCT) • 2nd trimester MA BP ≥ 90 mm Hg had +ve LR 3.5 and –ve LR 0.46 • BP remains the cornerstone of early diagnosis although it has limitations: • measurement errors associated with sphygmomanometer • effect of maternal posture on BP in pregnant women}.

20. Repeated routine urinalysis throughout pregnancy NOT useful for predicting PE • (JAMA 2003: 12;289(10):1220)

21. Uterine artery Doppler ultrasound • }impaired trophoblastic invasion of the spiral arteries: reduction in uteroplacental blood flow} • High pulsatility index and/or Notch in 1st & 2nd trimesters: poor predictor of PE(Papgeorghiou & Leslie, 2007) • Uterine artery Doppler plus biochemical markers • Promising results • Current data do not support this combination for routine screening for PE (Barton& Sibai, 2008).

22. Diastolic Notch in uterine artery waveform

23. The Roll over test Not of value in predicting PE (Mahomed &Lasiende,1990)

24. II. Biochemical Markers Angiogenic factors before& after the onset of PE (Barton& Sibai, 2008). Serum placental growth factor: reduced Soluble fms-like tyrosine kinase: elevated Endoglin: elevated

25. Conclusion • BP remains the cornerstone of early diagnosis • Markers • Reliability is inconsistent • Many suffer from poor specificity & predictive values. • None provided a cutoff value that could be clinically useful for the prediction of PE • (Widmer et al, 2007).

26. Currently: • There is no clinically useful screening test to predict PE(WHO, 2004)

27. Prevention of PE Primary Secondary

28. Primary prevention • Avoiding occurrence of the disease • Obese: • achieve an ideal b wt before conception (Villamor& Cnattingius, 2006) • No RCT • Ch hypertension: • Control BP before conception. • No RCT

29. Pregestational DM: • -Complete her family as early as possible & before vascular complications develop • -Control DM before conception & throughout pregnancy

30. Secondary • Breaking off the disease process before emergence of obvious clinical disease • {Etiology of the disease is unknown} • To correct theoretical pathophysiology • I. Non pharmacological • II. Nutritional • III. Pharmacological

31. I. Non pharmacological • Daily Bed rest • Rest for 4-6 h/d • May reduce risk of • PE for women with normal BP • (level 2 evidence) • (Cochrane Library 2006 Issue 2:CD005939)

32. 2. Life-style changes • High job stress: greater risk of PE(Sharma& Mittal, 2006) • Reducing job stress may be beneficial in the prevention of PE

33. 3. Regular prenatal exercise • May prevent or oppose progression (Weissgerber et al, 2004) • {Stimulation of placental growth • Reduction of oxidative stress • Reversal of maternal endothelial dysfunction}. • Insufficient evidence • Moderate intensity regular aerobic exercise • (Cochrane Library 2006 Issue 2:CD005942) • Aerobic exercise =cardiovascular exercise=any sustained rhythmic activity that involves large muscle groups: makes the lungs work harder as the body's need for oxygen is increased.

34. Stretching exercises are more effective at reducing the risk of PE than walking • (University of North Carolina,2008)

35. Smoking: • Reduced risk for PE (Sibai et al, 2005). • {Nicotine inhibition of interleukin-2 & tumor necrosis factor • Effects of nicotine on angiogenic proteins}. • Smoking: • abnormal fetal growth • preterm birth • Abruption • Adverse effects on maternal health.

36. II. Nutritional • 1. Higher total dietary fiber intake in early pregnancy may reduce risk for PE • (level 2 evidence) • Prospective cohort study • Am J Hypertens 2008 Aug;21(8):903

37. 2. Increasing dietary protein & energy intake RCT: no benefit • 5 or more servings of chocolate/w in 3rd trimester:40% reduction • (Triche, 2008; Epidemiology .19:459-464), Yale University • {Chocolate, especially dark chocolate, is rich in theobromine: stimulates the heart, relaxes smooth muscle & dilates blood vessels, and has been used to treat chest pain, high blood pressure}

38. 3. Garlic Insufficient evidence to recommend for preventing PE Cochrane Library 2006 Issue3:CD006065)

39. 4. Dietary sodium restriction • No significant differences • (Cochrane Library 2005 Issue 4:CD005548)

40. 6. Fish Oil Supplementation • Observational studies: beneficial effects • {inhibition of platelet thromboxane A2 without affecting prostacyclin: shifting the balance toward a reduced platelet aggregation and increased VD}. • RCT: No benefit • (Olsen et al, 2000) • High doses: increase the risk of PIH • (Olafasdottir et al, 2006). • Not recommended for the prevention of PE

41. 5. Weight Reduction • Although obesity is a known risk factor, there is no evidence that limiting wt gain during pregnancy; reduces its occurrence. • Wt reduction is not recommended during pregnancy even in obese women (Kramer, 2004)

42. III. Pharmacological • 1. Low-dose Aspirin • {inhibits biosynthesis of platelet thromboxane A2 with little effect on vascular prostacyclin production: altering the balance in favor of prostacyclin}. • (50-150 mg/day) • For women with a previous history of hypertension or PE (n=6,107): • Small to moderate benefits, safe. • level 2 evidence • (Cochrane Library 2007 Issue 2:CD004659)

43. 2. Low-dose Aspirin/Heparin • History of severe preterm PE & LBW infants. • (Sergio et al, 2006) • Lower incidence of PE (3Vs 30%) • Greater gestational age at delivery • Higher birth wt

44. 3. Calcium Supplementation • Reduces the risk of PIH, particularly in populations that have diets deficient in calcium • level 1 evidence(Cochrane Syt review , 2006) • The relationship between cal & risk of PIH is inconsistent& inconclusive • The relationship between cal & the risk of PE is highly unlikely. • Evidence-based review by FDA (2007)

45. 4. Antihypertensive Drugs • Mild to moderate hypertension: • Halving in the risk of developing severe hypertension • No difference in the risk of developing PE or proteinuria • (Cochrane syst review, 2007)

46. 5. Diuretics • No reduction in the incidence of PE or perinatal mortality • May have deleterious effects: • reduced renal & placental perfusion. • (Cochrane Library 2007 Issue 1:CD004451)

47. 6. Antioxidant supplementation may not affect risk of PE or clinical outcomes level 2 evidence (Cochrane Library 2008 Issue 1:CD004227)

48. 7. Concomitant Vit C& E supplementation • {PET: imbalance of oxidant & antioxidant activity: multiorgan endothelial dysfunction}. • Vit C (1,000 mg/d) plus vit E (400 IU/ d) • Did not prevent PE • level 2 evidence (Obstet Gynecol 2007 Dec;110(6):1311) • May increases rate of LBW infants& might be associated with higher rate of SB • level 2 evidence (Lancet 2006 Apr 8;367(9517):1145

49. 8. Magnesium • {Mg is beneficial for the prevention & tt of severe PE & E • Decreased intracellular Mg in PE} • No effect • (365 mg& 500 mg). • Cochrane syst review, 2004

50. 9. Folic acid& other B-vits • {Deficiency of vit B2 may cause biochemical changes simulating abnormalities of PE} • No evidence that any of B vits can prevent PE • (Shrama& Mittal, 2006).