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, 1991-1997) 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 < 100.000/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.

9

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 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)ObesityAtrterial abnormalities

Renovascular hypertensionCoarctation of the aorta

Endocrine diordersDiabetes mellitusCushing syndromePrimary aldosteronismPheochromocytomaThyrotoxicosis

Glomerulonephritis (acute and chronic)Renoprival hypertension

Chronic glomerulonephritisChronic renal insufficiencyDiabetic nephropathy

Connetive tissue diseaseLupus erythematosusSystemic sclorosisPeriarteritis nodosa

Polycystic kidney diseaseAcute 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)

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

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

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

Etiology

21

Abnormal Trophoblastic Invasion

In normal implantation, endovascular trophoblasts invade the uterine spiral arteries

22

23

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

Abnormal Trophoblastic Invasion

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

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)

Immunological Factors

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

PathogenesisVasospasm

Vascular constriction →resistance and subsequent hypertension

Maldistribution, ischemia of the surrounding tissues → blood flow → necrosis, hemorrhage, and other end-organ disturbances

31

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

32

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

Arachidonic acid

COX1,2

TXA2 PGI2, PGE2

Phospholipase A2

Platelet

35

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)

Increased Pressor Responses Nitric oxide

36

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)

Increased Pressor Responses Endothelins

37

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)

Increased Pressor ResponsesAngiogenic factors

38

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

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.

40

41

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)

Cardiovascular System Blood volume

42

43

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.

Cardiovascular System Blood volume

44

Blood and CoagulationPlatelet

Thrombocytopenia → life threatening Severe disease: < 100.000/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

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

Blood and CoagulationCoagulation

46

Severe preeclampsia – hemolysis

Peripheral blood change : Schizocytosis, spherocytosis, reticulocytosis

Blood and CoagulationFragmentation Hemolysis

47

Volume HomeostasisFluid 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 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 saving 가능 Blood T/F. Liver transplantation

Spontaneous hepatic rupture 의 mortality :30%

50

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. 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 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.

54

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

Rare 4hr to 8days

Visual disturbance

More common Retinal detachement

57

Brain

Cerebral Edema 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

Prediction Lots of attemption to predict preeclampsia in

early pregnancy -> poor sensitivity, poor positive predictive value

61

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

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

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

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

Antioxidants

Davidge, 1992 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%)

Prevention