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Prof. Aboubakr ElnasharBenha University Hospital, Egypt
•Prediction:Routine urine analysis•Prevention:Chocolate
Outline
IntroductionPredictionPrevention
Cochrane Systematic ReviewGold Standard' for high-quality systematic reviews
•Preeclampsia: Hypertension associated with proteinuria.
•Pathogenesis: •unknown (Barton& Sibai, 2008).
Impaired trophoblast differentiation& invasion Placental & endothelial dysfunction Immune maladaptation to paternal AgsExaggerated systemic inflam response.
•Pathogenesis: •Differs with various risk factors: PG Vs MG with previous PEpreexisting vas dispreexisting DM or multifetal gestation.
In PE: Impaired trophoblast differentiation & invasion
Placental and endothelial dysfunction
PREDICTION OF PE
• Why prediction is important?• The ideal screening test • Methods I. Preconception factors II. Pregnancy-Related Factors 1. Risk factors 2. Markers
Why prediction is important:1.The risk for recurrent PE can be as high as 65% (Barton&
Sibai, 2008).
2.PE is associated with substantial maternal& perinatal complications
The ideal Screening test: SimpleNoninvasiveRapidInexpensiveEasy to perform early in pregnancyHighly sensitivity & predictive.
I. Preconception factors1st 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).
Preconceptional Risk FactorsRates of preeclampsia depend on: severity of underlying
complications &
combinations of risk factors . Risk factorsRisk%
Chronic hypertension/renal disease15-40
Pre gestational DM10-35
Connective tissue disease (lupus, rheumatoid arthritis)
10-20
Thrombophilia (acquired or congenital) 10-40
Obesity/insulin resistance 10-15
Age older than 40 y10-20
Limited sperm exposure10-35
Family history of preeclampsia/ cardiovascular disease
10-15
Woman born as SFGA1.5 fold
Adverse outcome in a previous pregnancy: IUGR, ab placentae, IUFD
2-3 fold
II. Pregnancy-Related FactorsRegular 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 placentaMultifetal gestationUnexplained FGRGestational hypertensionUTIPeriodontal infectionMarkersBiophysicalBiochemical
Markers Many Based on: pathophysiological abnormalities
•SCREENING TESTS FOR PE (WHO, 2004)
I. Placental perfusion & vascular resistance dysfunctionMean arterial blood pressureRoll 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 dysfunctionHuman chorionic gonadotropin Alpha fetoprotein Estriol Inhibin A Pregnancy-associated plasma protein A Activin A Corticotropin release hormone
III. Renal dysfunction Serum uric acid Microalbuminuria Urinary calcium excretion Urinary kallikrein Microtransferrinuria N-acetyl- glucosarninidase
Platelet countPlatelet activation and endothelial cell adhesion moleculesProstacyclinCytokinesIsoprostanes, Antiphospholipid antibodies, Placenta growth factorHematocritAntithrombin IllCalciumTransferrinAtrial natriuretic peptide
Fibronectin Endothelin Thromboxane Homocysteine Serum lipids Insulin resistance Plasminogen activator inhibitor Leptin Total proteins Magnesium Ferritin Haptoglobin microglobulin Genetic markers
IV. Endothelial& oxidant stress dysfunction
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 sphygmomanometereffect of maternal posture on BP in pregnant women}.
•Repeated routine urinalysis throughout pregnancy NOT useful for predicting PE(JAMA 2003: 12;289(10):1220)
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).
Diastolic Notch in uterine artery waveform
The Roll over testNot of value in predicting PE
)Mahomed &Lasiende,1990(
II. Biochemical Markers
Angiogenic factors before & after the onset of PE(Barton& Sibai, 2008).
Serum placental growth factor: reducedSoluble fms-like tyrosine kinase: elevatedEndoglin: elevated
Conclusion•BP remains the cornerstone of early diagnosis •MarkersReliability is inconsistentMany 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).
•Currently: There is no clinically useful screening test to predict PE (WHO, 2004)
PrimarySecondary
Prevention of PE
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
•Pregestational DM:-Complete her family as early as possible & before vascular complications develop -Control DM before conception & throughout pregnancy
Secondary•Breaking off the disease process before emergence of obvious clinical disease•{Etiology of the disease is unknown} •To correct theoretical pathophysiology•I. Non pharmacologicalII. Nutritional III. Pharmacological
I. Non pharmacological1. Daily Bed restRest for 4-6 h/dMay reduce risk of PE for women with normal BP (level 2 evidence) (Cochrane Library 2006 Issue 2:CD005939)
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
3. Regular prenatal exercise•May prevent or oppose progression (Weissgerber et al, 2004)
•{Stimulation of placental growthReduction of oxidative stressReversal of maternal endothelial dysfunction}. •Insufficient evidenceModerate 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.
•Stretching exercises are more effective at reducing the risk of PE than walking (University of North Carolina,2008)
Smoking: Reduced risk for PE (Sibai et al, 2005).
{Nicotine inhibition of interleukin-2 & tumor necrosis factorEffects of nicotine on angiogenic proteins}. Smoking: abnormal fetal growthpreterm birthAbruptionAdverse effects on maternal health.
II. Nutritional1. 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
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}
3 .Garlic Insufficient evidence to recommend for preventing PE
Cochrane Library 2006 Issue3:CD006065
(
4. Dietary sodium restriction • No significant differences (Cochrane Library 2005 Issue 4:CD005548)
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
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)
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)
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 deliveryHigher birth wt
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& inconclusiveThe relationship between cal & the risk of PE is highly unlikely.Evidence-based review by FDA (2007)
4. Antihypertensive Drugs •Mild to moderate hypertension: Halving in the risk of developing severe hypertensionNo difference in the risk of developing PE or proteinuria (Cochrane syst review, 2007)
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)
6 .Antioxidant supplementation may not affect risk of PE or clinical outcomes
level 2 evidence
)Cochrane Library 2008 Issue 1:CD004227(
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 PElevel 2 evidence (Obstet Gynecol 2007 Dec;110(6):1311)•May increases rate of LBW infants& might be associated with higher rate of SBlevel 2 evidence (Lancet 2006 Apr 8;367(9517):1145
8. Magnesium •{Mg is beneficial for the prevention & tt of severe PE & EDecreased intracellular Mg in PE} •No effect•(365 mg& 500 mg).Cochrane syst review, 2004
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).
10. Zinc supplementation •{Zinc concentrations are reduced in PE}•RCT: No benefit(Jonsson et al, 1996)
11. Nitric oxide Insufficient evidence for preventing PECochrane Library 2007 Issue 2:CD006490
12. Progesterone Insufficient evidence for preventing PE Cochrane review, 2006
ConclusionRegular antenatal care is mandatory for the prevention & early detection of PE. For prevention of PEBed restReduction of job stressHigh dietary fiber intake Low dose aspirinLow dose aspirin/heparinCa supplementation
Thank YouThank YouThank YouThank YouAboubakr Elnashar