1. PREGNANCY INDUCED HYPERTENSION

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 (3201 in US, )
Black women are 3.1x to die as white women
Hypertensive disorders remain among the most significant and intriguing unsolved problems in obstetrics

4. Diagnosis Gestational hypertension Preeclampsia Eclampsia
Superimposed preeclampsia (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 ≥ 140/90 mmHg after 20 wks gestation
  - Proteinuria ≥ 300mg/24hrs or ≥1+ dipstick
￭ Increased certainty of preeclampsia
 - BP ≥ 160/110 mmHg
  - Proteinuria 2.0g/24hrs or ≥2+dipstick
 - Serum creatinine >1.2mg/dl unless known to be previously elevated
  - Platelets < /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 Worsening proteinuria
Epigastric or RUQ pain
Thrombocytopenia
severe vasospasm → microangiopathic hemolysis → Platelet activation, aggregation

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

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

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

12. Chronic Hypertension Chronic hypertension Underlying hypertension
BP decreases during the second and early third trimesters in both normotensive and chronically hypertensive women
Underlying hypertension
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

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. Incidence and Risk Factor
Nulliparous women
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

17. 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
BMI (Kg/m2)
Morbidity (%)
<19.8
4.3
>35
13.3
Gestation
twin 13
single 5
(Sibai, 2000)

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

19. 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

20. Etiology
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

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

23. 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

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

25. 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)

26. 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)

27. 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)

28. 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)

29. Genetic Factors
Hereditary hypertension is linked to preeclampsia (Ness, 2003)
Preeclampsia - eclampsia is highly heritable in sisters, daughters, granddaughter and daughters-in-law. (Chesley and Cooper, 1986)
60% concordance in monozygotic female twin pairs (Nilsson, 2004)
HLA-DR4 preeclampsia (Kilpatrick,1989)

30. Pathogenesis Vasospasm
Vascular constriction →resistance and subsequent hypertension
Maldistribution, ischemia of the surrounding tissues → blood flow → necrosis, hemorrhage, and other end-organ disturbances
Subsequent : 차후의

31. Pathogenesis Endothelial 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

32. Fig 34-3, (Friedman and Lindheimer, 1999)
Pathophysiological considerations in the development of hypertensive disorder due to pregnancy

33. 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)

34. 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

35. Increased Pressor Responses Nitric 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)

36. 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)

37. Increased Pressor Responses Angiogenic 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)

38. Pathophysiology Cardiovascular 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

39. Cardiovascular System Hemodynamic 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.

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

43. Cardiovascular System Blood 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 time after 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.

44. Blood and Coagulation Platelet
Thrombocytopenia → life threatening
Severe disease: < /uL
Platelet count → indication of delivery
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 thrombocytopenia (Prichard, 1987)

45. Blood and Coagulation Coagulation
PT, aPTT, fibrinogen level (routine lab assessment of coagulation) → preeclampsia management.
FDP: unknown (but, hepatic derangements (Leduc, 1992))
Thrombophilias :
Clotting factor deficiencies → early onset preeclampsia
Antithrombin
Preeclampsia (Chang, 1992)
Fibronectin
Glycoprotein-vascular endothelial cell basement membrane
Preeclampsia

46. Blood and Coagulation Fragmentation Hemolysis
Severe preeclampsia – hemolysis
Peripheral blood change :
Schizocytosis, spherocytosis, reticulocytosis

47. Volume Homeostasis Fluid and Electrolyte Changes
Preclampsia
ECF
Pathologic retension : endothelial injury
Electrolyte concentration do not differ.
Electrolyte unbalance
Vigorous diuretic therapy
Sodium restriction
Administration of water with sufficient oxytocin to produce antidiuretisis.
Following eclamptic convertion -> lower HCO3

48. Kidney Proteinuria Anatomical changes Preeclampsia-eclampsia Late.
24hr UA
Anatomical changes
Glomeruli : 20%
Glomerular capillary endotheliosis
Capillary endothelial swelling with subendothelial deposits of protein materials
Acute renal failure
Tubular necrosis, cortical necrosis -> oligouria, anuria, rapidly develped azotemia
HELLP synd. , placental abruption, postpartum hemorrhage

49. Liver
Periportal hemorrhagic necrosis in the periphery of the liver lobule
Serum liver enzyme
Nonfatal case
Hepatic rupture(more rare), subcapsular hematoma (more common).
Treatment
Surgical intervention, life saving가능
Blood T/F.
Liver transplantation
Spontaneous hepatic rupture 의 mortality :30%

51. Liver HELLP syndrome Hemolysis, Elevated Liver enzyme and Low Platelet
20% of severe preeclampsia and eclampsia
Adverse outcome : 40%
Other complication
Eclampsia (6%), Placental abruption (10%), ARF (5%), pulmonary edema (10%), subcapsular liver hematoma (1.6%)
Steroid Tx. - controversial

52. Brain Common Sx. Anatomical pathology
Headache, visual disturbance – associated convulsion (eclampsia)
Anatomical pathology
Gross hemorrhage – severe hypertension
Chronic hypertension
Postmortem cerebral lesion
Edema, hyperemia, focal anemia, thrombosis, hemorrhage

53. Brain Neuroimaging study CT MRI 50% abnormal finding
Hypodense cotical area – petechial hemorrhage and infarction site (at autopsy)
MRI
Cerebral artery area - remarkable change.
Convulsion
Convulsion: 25% cerebral infarction area.

55. Brain Cerebral Blood Flow
Eclampsia : loss of autoregulation of cerebral blood flow (Apollon, 2000)
Hyperperfusion – similar in hypertensive encephalopathy.
Increased cerebral perfusion –> headache
Cerebral vasospasm

56. Brain Blindness Visual disturbance Rare 4hr to 8days More common
Retinal detachement

57. Brain Cerebral Edema Electroencephalopgraphy Sx
Letharge, confusion, blurred vision, coma
Mental change, brain involvement. (CT, MRI)
Sudden severe blood pressure elevatoin
Electroencephalopgraphy

58. Uteroplacental perfusion
Vasospasm ->
placental perfusion -> perinatal mortality and morbidity
Measurement
Spiral a. : 500μm, 200 μm (preeclampsia)
Placental blood flow
Inaccesibility, complexity, unsuitablity
DHAS sulfate -> estradiol-17B (in placenta) clearance rate(Everett, 1980)

59. Uteroplacental perfusion
Doppler
Doppler measurement of blood velocity through uterine artery.
-> estimate uteroplacental blood flow

60. Prediction and Prevention
Lots of attemption to predict preeclampsia in early pregnancy -> poor sensitivity, poor positive predictive value

61. Lt. lat. Recumbent position -> supine position
Roll over test
28-32 wks
Lt. lat. Recumbent position -> supine position
Hypertension abnormal
Positive predictive value (true positive) : 33% (Dekker, 1990 ; Friedman and Lindhemier, 1999)

62. Weerasekera and Peiris (2003)
Uric acid
Decreased renal uric acid excretion -> elevated serum uric acid level
Jacobson (1990)
Uric acid level > 5.9mg/dL at 24wks ; positive predictive value : 33%
Weerasekera and Peiris (2003)
Serum uric acid levels did not vary significantly before the detection of hypertension

63. Clinical study, Paarlberg (1998)
Fibronectin
Endothelial cell activation -> elevated serum cellular fibronectin level (Brubaker, 1992)
Clinical study, Paarlberg (1998)
Low sensitivity : 69%
Positive predictive value :12%
Clinical study, Chavarria (2003)
16wks-20wks, 378 low-risk nulliparas
Positive predictive value : 29%
Negative predictive value : 98%

64. Oxidative Stress
Lipid peroxides level – antioxidants activity -> preeclampsia prediction (Walsh, 1994)
Marker
Lipid peroxides: malondialdehyde
Pro-oxidants : iron, transferrin, ferritin, blood lipids, TG, free fatty acid, lipoproteins, Vit C & E
Hyperhomocysteinemia
Atherosclerosis risk factor (non pregnant)

65. Released by vascular endothelium and leukocytes
Cytokines
Released by vascular endothelium and leukocytes
Interleukin, TNF – a
CRP
Not sufficiently predictive (Savvidou, 2002)

66. Placental peptides
Corticotropin releasing hormone, chorionic gonadotropin, activin A, inhibin A
Angiogenic factor: VEGF, PlGF

67. Fetal DNA
Identification of Fetal DNA in maternal serum -> prediction of preeclampsia (Zhong, 2001)
endothelial activation and inflammation

68. Uterine Artery Doppler Velocimetry
Second trimester – uteroplacental vascular resistance (by doppler of uterine artery)
Basic concepts
Impaired trophoblastic invasion of the spiral arteries -> uteroplacental blood flow
Bower (1993)
Sensitivity : 78%
Positive predictive value :28%

69. Prevention Dietary Manipulation
Salt restriction -> ineffective (Knuist, 1998)
Prenatal Ca supplementation -> significant reduction in BP and incidence of preeclampsia (Brucher, 1996)

70. Prevention Low dose aspirin
60mg aspirin → reduce the incidence of preeclampsia ; selective TXA2, dominence of endothelial prostacyclin (Hauth, 1998, Wallenburg, 1986)
Caritis, 1998; CLASP Collaborative Group, 1994; Hauth, 1993, 1998; Rotchell, 1998; Sibai, 1993a
Low-dose aspirin was ineffective in preventing preeclampsia

71. Prevention Antioxidants Davidge, 1992 Chappel, 1999
Markedly reduced antioxidant activity in preeclampsia women.
Chappel, 1999
283 high risk women
18-22wks , vit C & E versus placebo
Significant reduction in preeclampsia (11% / 17%)