1. Hypertensive Disorders in Pregnancy รองศาสตราจารย์ นายแพทย์ อติวุทธ กมุทมาศ

2. Scope • Terminology and classification • Risk factors • Etiology • Pathophysiology • Prediction and prevention • Management

3. Incidence • 3.7 % of pregnancies • 16% of pregnancy-related deaths • Eclampsia 1 in 2000 deliveries

4. Classificationby the working group of the NHBPEP (2000) • 1. Gestational hypertension • 2. Preeclampsia • 3. Eclampsia • 4. Preeclampsia superimposed on chronic hypertension (superimposed preeclampsia) • 5. Chronic hypertension

5. Gestationalhypertension • BP >= 140/90 mmHg for first time during pregnancy • No proteinuria • BP returns to normal < 12 wk postpartum • Final diagnosis made only postpartum • May have other S&S of preeclampsia , eg. epigastric discomfort or thrombocytopenia

6. Preeclampsia • Minimum criteria • BP >= 140/90 mmHg after 20 wk gestation • Proteinuria >= 300 mg/24hr or >=1+ dipstick • Mild preeclampsia • Severe preeclampsia

7. Severe preeclampsia • BP >= 160/110 mmHg • Proteinuria 5 g/24hr or >= 2+ dipstick (persistent) • Cr > 1.2 mg/dl • Platelets < 100,000 /mm3 • Microangiopathic hemolysis • Elevated ALT or AST • Persistent headache , visual disturbance , epigastric pain

8. Eclampsia • Seizures that cannot be attributed to other causes in a woman with preeclampsia • Seizures are generalized • May appear before , during or after labor • 10% develop after 48 hr postpartum

9. Superimposed preeclampsia • New onset proteinuria >= 300mg/24 hr in hypertensive women but no proteinuria before 20 wk • A sudden increase in proteinuria or BP or platelet count < 100,000 in women with hypertension and proteinuria before 20 wk

10. Chronichypertension • BP >= 140/90 mmHg before pregnancy or diagnosed before 20 wk , not attributable to GTD or • Hypertension first diagnosed after 20 wk and persistent after 12 wk postpartum

11. Diagnosis

12. GestationalHT • Also called transient HT • Final Dx : after delivery , by exclusion • BP : resting BP , Korotkoff phase V is used to defined diastolic pressure • GHT may later develop preeclampsia • 10% of eclamptic seizures develop before overt proteinuria is identified • BP rise , increase both mother and fetus risks

13. Preeclampsia • Described as “pregnancy-specific syndrome of reduced organ perfusion secondary to vasospasm and endothelial activation” • Proteinuria & glomerular pathology develop late in the course , pathophysiologic process begin as early as implantation

14. Preeclampsia • Diastolic hypertension >= 95 , increase fetal death rate 3 fold • Worsening proteinuria resulted in increasing preterm delivery • Epigastric pain from hepatocellular necrosis , ischemia and edema that stretches Glisson capsule • Thrombocytopenia from platelet activation & aggregation , microangiopathic hemolysis induced by severe vasospasm

15. Preeclampsia • Hemoglobinemia , Hburia , Hyperbilirubinemia : indicative of severe disease • Cardiac dysfunction , pulm edema , obvious IUGR : indicative of severe disease • Severity of preeclampsia assess by freq & intensity of abnormalities

16. Superimposed preeclampsia • 1. Hypertension (>=140/90) is documented antecedent to pregnancy • 2. Hypertension is detected before 20 wk , unless there is GTD • 3. Hypertension persists long after delivery • Additional previous Hx or family Hx of HT • End organ damage : LVH , retinal change • Risk abruption , IUGR , preterm & death

17. Underlying causes of CHT • Essential familial hypertension • Obesity • Arterial abnormalities • Endocrine disorders • Glomerulonephritis • Renoprival hypertension • Connective tissue disease • PCKD • ARF

18. Risk factorsfor preeclampsia • Nulliparous • Advanced maternal age • Race and ethnicity (genetic predisposition & envoronmental factor) • Multifetal gestation • Obesity • BMI > 35 kg/m2

19. Etiology • Theory account for the observation : hypertensive disorder more likely to develop in : • 1. exposed to chorionic villi for first time • 2. exposed superabundance of chorionic villi (Twin ,mole) • 3. Preexisting vascular disease • 4. Genetic predisposition

20. Etiology • 1. Abnormal trophoblastic invasion of uterine vessels • 2. Immunological intolerance between maternal and fetoplacental tissues • 3. Maternal maladaptation to cardiovascular or inflammatory changes of normal pregnancy • 4. Dietary deficiencies • 5. Genetic influences

21. Abnormal trophoblastic invasion • Normal implantation , uterine spiral arteries undergo extensive remodeling as they are invaded by endovascular trophoblasts • Incomplete invasion (decidual vessels , not myometrial vessels) : preeclampsia

22. Abnormal trophoblastic invasion

23. Atherosis : pathology • Endothelial damage • Insudation of plasma constituents into vessel walls • Proliferation of myointimal cells • Medial necrosis • Lipid accumulation in myointimal cells & macrophages • Aneurysmal dilatation • Obstruction of spiral arteriole

24. Placental growth factors : implications for abnormal placentation • Placental growth factors : regulate vascular endothelial cell and trophoblast function • Highly expressed in trophoblasts during normal pregnancy • Significantly decreased in preeclampsia • Asso with placental bed hypoxia & ischemia (Abnormal placentation) • J Soc Gyn Investig 2003 : 10 : 178-88

25. Placental protein 13 (PP-13) • PP-3 levels slowly increase during pregnancy • In 1st trimester , lower than normal were found in IUGR ,preeclampsia • In 2nd & 3rd trimester , higher than normal concentrations were found in preeclampsia , IUGR , preterm delivery • Used for assess risk to develop placental insuff • Placenta 2004 : 25 : 608-622

26. Immunological factors • Acute graft rejection • Impaired formation of blocking antibodies to placental antigenic sites • Lack of effective immunization in first pregnancies • Lower proportion of Th1 , Th2 dominance

27. Immunologic factors • Increased risk for first conception , new partner , conception very shortly after beginning sexual relation (5% if > 12mo) • Any kind of previous pregnancy (completed , spontaneous miscarriage or elective abortion) protective against preeclampsia • Tolerate semi-allogenic graft through father’s alloantigen • J. of Reprod Immunology 2003 (59) : 93-100

28. Immunological factors • IL10 regulate s arterial pressure in early primate pregnancy • IL-10 & TNFα : vasodilation of early pregnancy • Anti-human IL-10 MAb caused significant increase in MAP • TNF-α alone or combine with IL-10 not alter MAP • Cytokine 29 (2005) 176-185

29. Immunological factors • Serum from preeclamptic pt contains IgG autoantibody • Reacts with AT1 receptor • AT1-AA induce signaling in vascular cells and trophoblasts • Including AP-1 and NF-kB activation • Results in tissue factor production , reactive oxygen species (ROS)generation • Autoimmunity Reviews 4 (2005) : 61-65

30. Vasculopathy & inflammatory • Placental factors released by ischemic changes • Decidua activated , release noxious agents provoke endothelial cell injury • Endothelial cell dysfunction • Cytokines : TNFα , IL

31. Vasculopathy & inflammatory • Oxidative stress (ROS , free radical) self-propagating lipid peroxides formation • Generate highly toxic radicals injure endothelial cells • Modify NO2 production • Interfere PG balance

32. Vasculopathy & inflammatory • Oxidative stress : produce lipid-laden macrophage foam cells • Activation of microvascular coagulation : Thrombocytopenia • Increased capillary permeability : proteinuria and edema

34. Angiogenic growth factors & HT • HT : disease of inadequate or aberrant responses to angiogenic growth factors • Preeclampsia is accompanied by high circulating levels of soluble VEGF receptor-1 (inactive complexes with VEGF + plGF) • High AGF : contribute to peripheral & pulm edema , microalb , progression of atherosclerosis • Angiogenesis 7 : 2004 : 193-201

35. Prostaglandin • Platelet activation : hallmark of SPE • Platelet PGH synthase 1-derived (PGHS1-derived) & TxA2 • Low dose aspirin treatment decreased platelet aggregation & prevented thrombosis • Decrease progesterone during parturition : sustain parturition • J of Clin Inv , April 2005 : 115 : 986-995

36. PS/PC induce preeclampsia • Phosphatidylserine (PS) 80% / Phosphatidylcholine (PC) 20% • Significant elevation in SBP • Significant increase in TAT levels • Significant decrease platelet counts • Significant increase proteinuria • Significant reduction in fetal & placental weight • Semin Thromb Hemost. Jun2005 : 31 : 34-20

37. Endothelin-1 • Increased ET-1 in amniotic fluid & plasma of infant and mother in preeclampsia • Asso with abnormal placentation • J Vet Intern Med. 2005 Jul-Aug : 19 : 594-8

38. Nutritional factors • Dietary taboos : meat , protein , purines , fat , dairy products , salt • Supplement of Zn , Ca , Mg prevent preeclampsia ? • Fruits & vegetables : antioxidant • Ascorbic acid intake < 85 mg/d , predispose preeclmapsia 2 fold • Obesity increase risk preeclampsia

39. Genetic factors • Hereditary hypertension, preeclampsia , eclampsia • Polygenic inheritance • Asso with HLA-DR4 • Maternal Ab against fetal anti HLA-DR Ig • Heterozygous for angiotensinogen gene variant T235 • Polymorphisms of genes for TNF , IL 1β , Lymphotoxin α

40. Genetics of preeclampsia • Familial predisposition • AGT(encode angiotensinogen) & NOS 3 (encode nitric oxide synthestase) genes mutation • Clin Genet 2003 : 64 : 96-103

41. Is preeclampsia an infectious disease? • Analyze IgG Ab against HSV-2 , CMV , EBV , Toxoplasma gondii at first ANC • Seronegative for HSV-2, CMV , EBV increased risk preeclampsia (OR 1.7 ,1.6, 3.5) • Seronegative for Toxo not associated with increase risk preeclampsia (OR 1.0) • Acta Obstet Gynecol Scand 2001 : 80 : 1036-8

42. Pathogenesis • Vasospasm • Endothelial cell activation • Increased pressor resonses • Prostaglandins • Nitric oxide • Endothelins • Angiogenic factors (VEGF , PIGF)

43. Pathogenesis • Increased vascular reactivity to vasopressor • Decrease PG I2 production by endothelium • Increase TxA2 secretion by platelet • Increased NO2 synth by endothelium • Decrease NO2 synthease

44. Comparison of mean ATII infusion doses required to evoke a pressor response

45. Pathophysiology • Endothelial damage • Interstitial leakage • Platelet & fibrinogen deposit • Increase subendothelial a. resistance • Decreased blood flow • Ischemia necrosis , hemorrhage • Multiorgan involvement

46. Cardiovascular system • Increase after load • Preload diminish • Endothelial activation with extravasation • Decreased cardiac output • Hemoconcentration from generalized vasoconstriction and endothelial dysfynction • Decreased blood volume

47. Blood and coagulation • Thrombocytopenia from platelet activation , aggregation & consumption • Increased plt activating factor & thrombopoietin • Clotting factors decrease • Erythrocytes rapid hemolysis (increase LDH , schizocyte , MAHA)

48. Volume homeostasis • Decrease plasma levels of renin , AT II , aldosterone • DOC increase • Vasopressin normal despite decreased plasma osmolality • ANP increased • Extracellular fluid : edema : endothelial injury , reduced oncotic pressure

49. Kidney • RPF & GFR reduced • Uric acid elevated • Creatinine clearance reduced , oliguria • Diminished urinary Ca due to increased tubular reabsorption • Urine sodium elevated • Urine osmolality , U:P Cr , FE Na : prerenal mechanism

50. Kidney • Proteinuria : glomerulopathy : increased permeability : albumin , Hb , globulin , transferins • Anatomical changes : glomeruli enlarge , capillary loops dilated & contracted , endothelial cells swollen fibrils deposit (glomerular capillary endotheliosis)