Hypertensive Disorders in Pregnancy (I)

1. Hypertensive Disorders in Pregnancy (I) Williams Obstetrics 22nd Edition Chapter 34 부산백병원 산부인과 조인호

2. Index • Diagnosis • Etiology • Pathogenesis • Pathophysiology • Prediction and Prevention • Management • Long-term consequences

3. Gestational Hypertension – 3.7% in 150,000 (National Center for Health Statics, 2001) • Pregnancy-related hypertension : • Pregnancy-related deaths(3201명 in US, 1991-1997)의 16% 차지 • Black women are 3.1 times to die as white women • Hypertensive disorders remain among the most significant and intriguing unsolved problems in obstetrics

4. Diagnosis • Gestational hypertension • Preeclamsia • Eclamsia • Superimposed preeclamsia (on chronic hypertension) • Chronic hypertension

5. Gestational hypertension • BP≥ 140/90mmHg for first time during pregnancy • No proteinuria • BP returns to normal < 12 weeks’ postpartum • Final diagnosis made only postpartum • May have other signs or symptoms of preeclampsia, for example, epigastric discomfort or thrombocytopenia

6. Preeclampsia ￭ Minimum Criteria   - BP≥140/90mmHg after 20weeks' gestation   - Proteinuria ≥300mg/24hrs or ≥1+dipstick ￭ Increased certainty of preeclampsia   - BP≥160/110mmHg   - Proteinuria 2.0g/24hrs or ≥2+dipstick   - Serum creatinine >1.2mg/dl unless known to be previously elevated   - Platelets <100000/mm3   - Microangiopathic hemolysis (Increased LDH)   - Elevated ALT or AST   - Persistent headache or other cerebral or visual disturbance   - Persistent epigastric pain

7. Preeclampsia • Diastolic hypertension ≥95mmHg • Fetal death rate : 3배이상 증가 • Worsening proteinuria • preterm labor 증가 • Neonatal survival 변화없음 • Epigastric or RUQ pain • Hepatocellur necrosis, ischemia, edema that stretches the Glisson capsure • AST/ALT상승 : 임신종결의 sign • Hepatic rupture : rare • Thrombocytopenia • severe vasospasm -> microangiopathic hemolysis -> Platelet activation, aggregation

8. Severity of Preeclampsia • Rapid increase in BP followed by convulsions is usually preceded by unrelenting severe headache or visual disturbances. • Differentiation between mild & severe preeclampsia can be misleading -because apparently mild disease may progress rapidly to severe disease

10. Eclampsia • preeclampsia+convulsion • Seizures that cannot be attributed to other causes in woman with preeclampsia • Seizures are generalizedand may appear before, during, of after labor

11. Chronic hypertension • BP ≥140/90 mmHg before pregnancy or diagnosed before 20weeks’ gestation (not attributable to gestational trophoblastic disease) or • Hypertension first diagnosed after 20weeks’ gestation and persistent after 12weeks’ postpartum

12. Chronic Hypertension • Chronic hypertension은 임신후반기까지 진단하기 어려움. • 이유: BP decreases during the second and early third trimesters in both normotensive and chronically hypertensive women • Underlying hypertension의 원인 • Essential familial hypertension (90%)

13. Underlying Causes of Chronic hypertensive Disorder Essential familial hypertension (hypertensive vascular disease) Obesity Atrterial abnormalities Renovascular hypertension Coarctation of the aorta Endocrine diorders Diabetes mellitus Cushing syndrome Primary aldosteronism Pheochromocytoma Thyrotoxicosis Glomerulonephritis (acute and chronic) Renoprival hypertension Chronic glomerulonephritis Chronic renal insufficiency Diabetic nephropathy Connetive tissue disease Lupus erythematosus Systemic sclorosis Periarteritis nodosa Polycystic kidney disease Acute renal failure

14. Chronic Hypertension • Chronic HT • → ventricular hypertrophy, cardiac decompensation, cerebrovascular accidents, renal damage • 임신 때 superimposed preeclampsia가 생기는 경우(최고 25%까지 보고됨, 1998, Sibai) 위의 합병증들이 더욱 호발함.

15. Preeclampsia superimposed on Chronic Hypertension • New-onset proteinuria≥ 300mg/24hours in hypertensive women but no proteinuria before 20 weeks’ gestation • A sudden increase in proteinuria or blood pressure or platelet count <100,000/mm3 in women with hypertension and proteinuria before 20weeks’ gestation

16. Superimposed preeclampsia • Placental abruption, growth restriction, preterm delivery, death 의 위험성이 증가 • 일반적으로 “Pure” preeclampsia에 비해 증상이 훨씬 severe하고 종종 fetal growth restriction이 동반된다.

17. Incidence and Risk Factor • Nulliparous women에게 흔함. • Incidence : 5% (wide variation) • Influence by • Parity, race, ethnicity, genetic predisposition • Nulliparous • Total :7.6% / severe : 3.3% (Hauth, 2000) • Risk factor • Chronic hypertension, multifetal gestation, maternal old age(>35 yrs), obesity, African-American ethnicity

18. Incidence and Risk Factor • Maternal weight and the risk of preeclampsia is progressive. • Smoking during pregnancy reduced risk of hypertension during pregnancy (Bainbridge,2005 ; Zhang, 1999) • Placenta previa also reduced the risk of hypertension (Sibai, 2000)

19. Incidence and Risk Factor(Eclampsia) • Eclampsia • Somewhat preventable • Receive adquate prenatal care • 1976 (williams Obstetrics 15th edition) • 1/700 deliveries (Parkland Hospitial) • 1983-1986 • 1/1150 deliveries • 1999 • 1/1750 deliveries • 2000, National Vital Statistics Report, in US • 1/3250 • 1994, Douglas and Redman in UK • 1/2000

20. Etiology • Basic concepts • Exposed to chorionic villi for the first time • Exposed to a superabundance of chorionic villi, as with twins or hydatidiform mole • Have preexisting vascular disease • Genetically predisposed to hypertension developing during pregnancy

21. Vascular endothelial damage with vasospasm, transudation of plasma, and ischemic and thrombotic sequelae. • Currently plausible potential cause (2003, Sibai) • Abnormal trophoblastic invasion of Uterine vessels • Immunological intolerance between maternal and fetoplacental tissues • Maternal maladaptation to cardiovascular or inflammatory changes of normal pregnancy • Diatary deficiencies • Genetic influences

22. Abnormal Trophoblastic Invasion • In normal implantation, endovascular trophoblasts invade the uterine spiral arteries

24. Abnormal Trophoblastic Invasion • In preeclampsia • Incomplete trophoblastic invasion • The magnitude of defective trophoblastic invasion of the spiral arteries correlated with the severity of the hypertensive disorder (2000, Madazli) • Using electron micorscopy • Endothelial damage • Insudation of plasma constituents into vessel walls • Proliferation of myointimal cells • Medial necrosis • Lipid and macrophage accumulates in myointimal cells

25. Lipid-laden cells -> atherosis (Hertig, 1945) • Obstruction of the spiral arteriolar lumen by atherosis may impair placental blood flow • Placental perfusion -> diminished

26. Immunological Factors • Theory • Formation of blocking antibodies of placental antigenic sites might be impaired. • Number of antigenic sites provided by the placenta is unusually great compared with the amount of antibody, as with multiple fetuses. (Beer, 1978) • Effective immunization by a previous pregnancy is lacking, as in first pregnancies. • The immunization concept was supported by • their observations that preeclampsia developed less often in multiparas who had a prior term pregnancy (Mostello, 2002; Trupin, 1996)

27. Immunological Factors • Early second timester - Develop preeclampsia women • Lower proportion of helper T cells (Th1) • Th2 dominance, mediated by adenosine, which is found in higher serum level in preeclamptic compared with normotensive women (Yoneyama, 2002) • These helper T lymphocytes secrete specific cytokines that promote implantation, and their dysfunction may favor preeclampsia (Hayashi, 2004; Whitecar, 2001)

28. The Vasculopathy and the Inflammatory Changes • The decidua contains an abundance of cells that, when activated, can release noxious agents. (Staff, 1999) -> mediators to provoke endothelial cell injury • Preeclamsia due to an extreme state of activated leukocytes in the maternal circulation (Faas, 2000) • Cytokines : TNF-a, interleukin → oxidative stress (highly toxic radicals) • Potential benefit of antioxidants to prevent preeclampsia(Chappell, 1999; Zhang, 2002)

29. Nutritional Factors • Dietary deficiencies and Excesses over the centuries have been blamed as the cause of eclampsia. • Supplementation with various elements such as zinc, calcium, and magnesium to prevent preeclampsia(John, 2002) • Obesity, is a potent risk factor for preeclampsia • C-reactive protein, an inflammatory marker, was shown to be increase in obesity, which in turn was associated with preeclampsia (Wolf, 2001)

30. Genetic Factors • Hereditary hypertension is linked to preeclampsia (Ness, 2003) • Preeclampsia- eclampsia is highly heritable in sisters, daughters, granddaughters, and daughters-in-law. (Chesley and Cooper, 1986) • 60% concordance in monozygotic female twin pairs(Nilsson, 2004) • HLA-DR4와 preeclampsia와의 연관성(kilpatrick,1989)

31. PathogenesisVasospasm • Vascular constriction→resistance and subsequent hypertension • Maldistribution, ischemia of the surrounding tissues → blood flow의 감소→ necrosis, hemorrhage, and other end-organ disturbances

32. PathogenesisEndothelial cell activation • Unknown factors (from placenta) are secreted into the maternal circulation → activation and dysfunction of the vascular endothelium. • Damaged or activated endothelial cells secrete substances → promote coagulation and increase the sensitivity to vasopressors →changes in glomerular capillary endothelial morphology →increasd capillary permeability →elevated blood concentrations

34. Increased Pressor Responses • Normally, pregnant women develop refractoriness to infused vasopressors(Abdul-Karim an Assali, 1961) • But, early preeclampsia women have increased vascular reactivity to infused norepinephrine and angiotensin II(Raab, 1956)

36. Increased Pressor Responses Prostaglandins • In preeclampsia • Endothelial prostacyclin (PGI2) production is decreased • Thromboxane A2(TXA2) secretion by platelets is increased → Increased sensitivity to infused angiotensin II → vasoconstriction Membrane phospholipid Phospholipase A2 Arachidonic acid COX1,2 PGI2, PGE2 TXA2 Platelet

37. Increased Pressor ResponsesNitric oxide • Synthesized from L-arginine by endothelial cells. (potent vasodilator) • Nitric oxide maintains the normal low-pressure vasodilated state characteristic of fetoplacental perfusion(Myatt, 1992) • Preeclampsia is associated with decreased endothelial nitric oxide synthase expression, which increases cell permeability(Wang, 2004)

38. Increased Pressor Responses Endothelins • Endothelin-1 (ET-1) : • potent vasoconstrictors • Produced by human endothelium • Plasma ET-1 is increased in normotensive pregnant women, but women with preeclampsia have even higher levels (Ajne, 2003 ; Clark, 1992)

39. Increased Pressor ResponsesAngiogenic factors • Vascular endothelial growth factor (VEGF), Placental growth factor (PIGF), • which secretion increases in normal pregnancy • Promote angiogenesis • Induce nitric oxide • Vasodilatory prostaglandins • Paradoxically, VEGF is increased in serum from women with preeclampsia, but its bioavailability is decreased (Baker, 1995 ; Simmons, 2000)

40. PathophysiologyCardiovascular System • Increased cardiac afterload caused by hypertension • Cardiac preload in preeclampsia • Pathologically diminished hypervolemia of pregnancy • Iatrogenically increased by iv crystalloid or oncotic solution • Extravasion into the extracellular space, especially the lung

41. Cardiovascular SystemHemodynamic Changes • Preeclampsia • Cardiac output elevated before hypertension developed than normal pregnancy. • With clinical onset of preeclampsia • Marked reduction in cardiac output. • Increased peripheral resistance. • By contrast, Gestational hypertension • Elevated cardiac outputs with development of hypertension.

43. (Hankin, 1984)

44. Cardiovascular SystemBlood volume • Blood volume in term • Normal pregnancy : 5000ml • Not pregnancy : 3500ml • Eclampsia : 3500ml • Hemoconcentration in preeclampsia • Vasoconstriction and Endothelial dysfunction with vascular permeability. • Sevirity 와연관되어 있지 않음. • Whereas, gestational hypertension have a normal blood volume (Silver, 1998)

46. Cardiovascular SystemBlood volume • With severe hemoconcentration, an acute fall in hematocrit suggested resolution of preeclampsia • Intravascular compartment in eclamptic women is usually not underfilled. → vasospasm and endothelial leakage of plasma has contracted the space to be filled. → It persist some timeafter delivery when the vascular endothelium repairs. • Sensitive to vigorous fluid therapy to expand the contracted blood volume to normal pregnancy levels. • Sensitive to even normal blood loss at delivery.

47. Blood and CoagulationPlatelet • Thrombocytopenia → life threatening • Severe disease : < 100,000/uL • Platelet count 감소 -> indication of delivery -> 분만 후 3-5 days, 정상수준으로 회복 • Platelet activation, aggregation, consumption -> “exhausion” -> thrombocytopenia(Harlow, 2002) • HELLP syndrome : hemolysis (H) , elevated liver enzymes (EL), and low platelets (LP) (Weinstein, 982) • Neonatal thrombocytopenia • Maternal thrombocytopenia와 연관이 없음. (Prichard, 1987)

48. Blood and CoagulationCoagulation • PT, aPTT, fibrinogen level (routine lab assessment of coagulation) -> preeclampsia 의 management에 필요하지 않음. • FDP의 증가 : unknown (but, hepatic derangements 때문일 것으로 추정(Leduc, 1992) ) • Thrombophilias : • clotting factor deficiencies -> early onset preeclampsia • Antithrombin 을 투약하면 대조군에 비해 preeclampsia의 발생빈도를 낮출 수 있음(Chang, 1992) • Fibronectin • Glycoprotein-vascular endothelial cell basement membrane • Preeclampsia의 예측인자로 활용

49. Blood and CoagulationFragmentation Hemolysis • Severe preeclampsia 때 LDH의 증가 – hemolysis의 증거 • Peripheral blood change : • Schizocytosis, spherocytosis, reticulocytosis

50. Volume HomeostasisEndocrine changes • Renin, angiotensin, aldosterone • 정상 임신에서는 증가 • But, preeclampsia에서는 비임신의 정상 level로 감소 • 기전 : Na + retension, hypertension 에 의해 • Juxtaglomerular apparatus에서 renin분비가 감소 • Angiotensinogen이 angiotensin I 으로 conversion (renin의 작용) 이 감소 • Angiotensin II의 감소 -> aldosterone의 감소 • 이런 상황에도 불구하고 preeclampsia 산모에서 Na retension이 계속 된다. (Brown, 1988)