hypertensive disorders in pregnancy (williams 22 edition)

Hypertensive Disorders in Pregnancy

Index

Diagnosis

Etiology

Pathogenesis

Pathophysiology

Prediction and Prevention

Management

Gestational Hypertension - 3.7% in 150,000 (National Center for Health Statics, 2001)

Pregnancy-related hypertension: Pregnancy-related deaths (16% of 3201 in US, 1991-1997)

Black women are 3.1 times to die as white women

Hypertensive disorders remain among the most significant and intriguing unsolved problems in obstetrics

INTRODUCTION

Williams Obstetric 22 edition, Chapter 34: Hypertensive Disorders in Pregnancy

Diagnosis

Etiology

Pathogenesis

Pathophysiology


Management

Index

Diagnosis

Gestational hypertension

Preeclamsia

Eclampsia

Superimposed preeclamsia (on chronic

hypertension)

Chronic hypertension


Gestational hypertension

BP≥ 140/90mmHg for first time during pregnancy

No proteinuria

Blood Pressure 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


Pre-eclampsia:Pre-eclampsia:a multisystem a multisystem disorderdisorder

PreeclampsiaMinimum 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


PreeclampsiaDiastolic hypertension ≥ 95mmHg

Increase fetal death rate (38000 prenancy in 1976)

Worsening proteinuria Increasing preterm deliveryNeonatal survival was not significantly altered.

Epigastric or RUQ painHepatocelular necrosis, ischemia, edema that stretches the Glisson capsureAST / ALT elevated signHepatic rupture: rare

ThrombocytopeniaSevere vasospasm Microangiopathic hemolysis Platelet activation, aggregation Williams Obstetric 22 edition, Chapter 34: Hypertensive Disorders in Pregnancy

PathophysiologyPreeclampsia

The Texbook’s Kidney Disease and Hypertension in Pregnancy, 2003

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


Indications of Severity of Hypertensive Disorder during Pregnancy


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


Chronic hypertension

BP ≥140/90 mmHg before pregnancy or diagnosed before 20 weeks gestation (not attributable to gestational trophoblastic disease)

or

Hypertension first diagnosed after 20 weeks gestation and persistent after 12 weeks postpartum


Underlying Causes of Chronic hypertensive Disorder

Essential familial hypertension (hypertensive vascular disease)ObesityAtrterial abnormalities

Renovascular hypertensionCoarcta tion of the aorta

EndocrinedisordersDiabetes 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


Chronic Hypertension

Chronic Hypertension can lead: Ventricular hypertrophy, Cardiac decompensation, Cerebrovascular accidents, renal damage

That complication are more likely during pregnancy if there is superimposed preeclampsia (which 25% of these women, 1998, Sibai).


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


Superimposed Preeclampsia

Placental abruption, growth restriction, preterm delivery, death. These complication of Superimposed Preeclamsia.

Develops earlier than “Pure” preeclampsia, and it tends to be more severe and often accompanied by fetal growth restriction.


Incidence and Risk Factor

Nulliparous women.Incidence: 5% (wide variation)Influence by

Parity, race, ethnicity, genetic predisposition

NulliparousTotal:7.6% and severe: 3.3% (Hauth, 2000)

Risk factorChronic hypertension, multifetal gestation, maternal old age (>35 yrs), obesity, African-American ethnicity


Incidence and Risk FactorMaternal 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)


Incidence and Risk Factor (Eclampsia)

EclampsiaSomewhat preventable

Receive adquate prenatal care

1976 (williams Obstetrics 15th edition)1/700 deliveries (Parkland Hospitial)

1983-19861/1150 deliveries

19991/1750 deliveries

2000, National Vital Statistics Report, in US1/3250

1994, Douglas and Redman in UK1/2000


Diagnosis

Etiology

Pathogenesis

Pathophysiology


Management

Index

Etiology

Basic conceptsExposed 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


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


Physiology Cythotrophoblast Invasion


Invasion Cytotrophoblast Cells


Abnormal Trophoblastic Invasion

In normal implantation, endovascular trophoblasts invade the uterine spiral arteries

Normal placental implantation shows proliferation of extravillous trophoblasts


In PreeclamsiaIncomplete trophoblastic invasionThe magnitude of defective trophoblastic invasion of the spiral arteries correlated with the severity of the hypertensive disorder (2000, Madazli)

Using Electron MicorscopyEndothelial damageInsudation of plasma constituents into vessel wallsProliferation of myointimal cellsMedial necrosisLipid and macrophage accumulates in myointimal cells

Abnormal Trophoblastic Invasion


Lipid-laden cells atherosis (Hertig, 1945)

Obstruction of the spiral arteriolar lumen by atherosis may impair placental blood flow

Placental perfusion diminished


ISKEMIC PLACENTA

O2

O2 radical

OH- radikal

H2O2

SEL ENDOTHEL

PROTEINMEMBRANE

NUKLEUS

Peroksida lipid

Disfunctions of Endothel


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 preeclampsiaC-reactive protein, an inflammatory marker, was shown to be increase in obesity, which in turn was associated with preeclampsia (Wolf, 2001)


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-DR reported an association preeclampsia and proteinuric hypertension (kilpatrick,1989)


Diagnosis

Etiology

Pathogenesis

Pathophysiology


Management

Index

Pathogenesis Vasospasm

Vascular constriction resistance and subsequent hypertension

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


Vasospam Spiral Arteries


Pathophysiology VasospasmFailure of Cytotrophoblast invasion of the spiral arteries

Vasocontriction spiral arteries


The Complication of Vasospasm


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


Increased Pressor ResponsesProstaglandins

In PreeclampsiaEndothelial prostacyclin (PGI2) production is decreased

Thromboxane A2 (TXA2) secretion by platelets is increased

Increased sensitivity to infused angiotensin II

vasoconstriction

PlateletsThe Texbook’s Kidney

Disease and Hypertension in Pregnancy, 2003

Diagnosis

Etiology

Pathogenesis

Pathophysiology


Management

Index

Pathophysiology Vascular Changes in Pregnancy

Dewhurst's Textbook of Obstetrics and Gynaecology 7th Edition

PathophysiologyCardiovascular System

Increased cardiac afterload caused by hypertension

Cardiac preload in preeclampsiaPathologically diminished hypervolemia of pregnancy

Iatrogenically increased by iv crystalloid or oncotic solution

Extravasion into the extracellular space, especially the lung


Cardiovascular SystemHemodynamic Changes

PreeclampsiaCardiac output elevated before hypertension developed than normal pregnancy.

With clinical onset of preeclampsiaMarked reduction in cardiac output.Increased peripheral resistance.

By contrast, Gestational hypertensionElevated cardiac outputs with development of hypertension.


Severe Preeclamsia and Eclampsia: Associated Hemodynamic Measurements


(Hankin, 1984)

Ventricular Function in Severe Preeclampsia-Eclampsia


Blood volume in termNormal pregnancy: 5000mlNot pregnancy: 3500mlEclampsia: 3500ml

Hemoconcentration in preeclampsiaVasoconstriction and Endothelial dysfunction with vascular permeability.Depending on severity, hemoconcentration is usually not as marked.Whereas, gestational hypertension have a normal blood volume (Silver, 1998)

Cardiovascular SystemBlood Volume


Comparing nonpregnant Mean Blood Volume


Blood and CoagulationPlatelet

Thrombocytopenia life threatening

Severe disease: < 100,000/uL

Platelet count continues to decrease indication of delivery the platelet count increases progressively after delivery (within 3 to 5 day)Platelet activation, aggregation, consumption “exhausion” thrombocytopenia (Harlow, 2002)

HELLP syndrome: hemolysis (H) , elevated liver enzymes (EL), and low platelets (LP) (Weinstein, 982)


Volume HomeostasisEndocrine changes


Deoxycorticosterone (DOC)Another potent mineralocorticoid

Increses 3rd trimesterResult from conversion plasma progesterone rather than increased maternal adrenal secretion.

DOC is not reduced by sodium retention or hypertension

DOC may serve to explain why women with preeclamsia retain sodium.

Volume HomeostasisEndocrine changes


The Physiology Kidney of Pregnancy


Pathophysiology Hipertension in Preeclampsia


Functional Renal Alterations in Preeclampsia


Functional Renal Alterations in Preeclampsia (Continued)


Functional Renal Alterations in Preeclampsia (Continued)

The Texbook’s Kidney Disease and Hypertension in

Pregnancy, 2003

LiverPeriportal hemorrhagic necrosis in the periphery of the liver lobule

Serum liver enzyme is elevatedHepatic rupture (more rare), subcapsular hematoma (more common).Treatment

Surgical intervention may be life savingBlood transfusion (recombinant VIIa) to help control heptic haemorrhage. Liver transplantation.

Spontaneous hepatic rupture in 121 cases and mortality rate was 30%


Gross Liver specimen from a woman with Preeclampsia


Liver

HELLP syndromeHemolysis, Elevated Liver enzyme and Low Platelet

20% of severe preeclampsia and eclampsia

Adverse outcome: 40%

Other complicationEclampsia (6%), Placental abruption (10%), ARF (5%), pulmonary edema (10%), subcapsular liver hematoma (1.6%)

Steroid Theraphy - controversial


Differential Diagnosis of Microangipathic Syndrome During Pregnancy


Brain

Common SubjectifHeadache, visual disturbance - associated convulsion (eclampsia)

Anatomical pathologyGross hemorrhage - severe hypertension

These complications in women with underlying chronic hypertension

Postmortem cerebral lesionEdema, hyperemia, focal anemia, thrombosis, hemorrhage.


Brain

Neuroimaging studyCT

All women with eclampsia have abnormal brain finding

Hypodense cotical area – petechial hemorrhage and infarction site (at autopsy)

MRIDescribed remarkable changes in the posterior Cerebral artery area.

25% of women with eclampsia have areas of cerebral infarction


MRIs performed 6 weeks after delivery complicated by eclampsia

Magnetic Resonance Imaging

Brain

Cerebral Blood FlowEclampsia loss of autoregulation of cerebral blood flow (Apollon, 2000)

Hyperperfusion similar in hypertensive encephalopathy.

Increased cerebral perfusion headache.


BrainBlindness

It rare with preeclampsia alone

It follow eclamptic convulsions in up 10% of women

Develop up to a week or more following delivery (Chambers and Cain, 2004)

Vasogenic edema of occipital lobe on MRI and CT

Permanent visual defect, including blindness caused by Cerebral infarction (retinal artery ischemia) (Moseman and Shelton,2002)

Retinal detachment may also altered vision


BrainCerebral Edema

SubjectifLetharge, confusion, blurred vision to obtundation and, coma

Mental status change correlated with brain involvement seen with CT and MRI studies

Sudden severe blood pressure elevatoinsVasogenic edema

Blood pressure control.

ElectroencephalopgraphyReported that 75% of 65 women with eclampsia had abnormal finding within 48 hours of seizure.


Uteroplacental perfusion

Vasospasm Placental perfusion from vasospasm increases perinatal mortality and morbidity

MeasurementSpiral artery 500μm (normal), 200 μm (preeclampsia)

Placental blood flowInaccesibility, complexity, and unsuitablity


Uteroplacental Perfusion cause Hypertension

http://hyper.ahajournals.org/cgi/content/full/38/3/718

Uteroplacental Perfusion

Doppler

Doppler measurement of blood velocity through uterine

artery estimate uteroplacental blood flow

Vascular resistance is estimated by comparing arterial

systolic and distolic velocity waveforms

Abnormal waveforms fetal indication required sectio

cesarean

HELLP syndrome 18-36% abnormal waveforms


Fetal Velocity Waveforms

Medical Physiology Lippincott Williams & Wilkins, 2nd edition 2004

Diagnosis

Etiology

Pathogenesis

Pathophysiology


Management

Index


PredictionLots of attemption to predict preeclampsia in early pregnancy poor sensitivity, poor positive predictive value


Roll over testHypertensive respone induce by having women at 28 to 32 weeks

Lying laterally Recumbent position supine position

Hypertension abnormal

Positive predictive value (true positive) : 33% (Dekker, 1990 ; Friedman and Lindhemier, 1999)

Prediction (Continued)


FibronectinEndothelial cell activation elevated serum cellular fibronectin level (Brubaker, 1992)

Clinical study, Paarlberg (1998)Low sensitivity: 69%

Positive predictive value: 12%

Clinical study, Chavarria (2003)16 weeks - 20 weeks, 378 low-risk nulliparas


Negative predictive value: 98%



Oxidative StressLipid peroxides level increases descreases antioxidants activity preeclampsia prediction (Walsh, 1994)

MarkerLipid peroxides: malondialdehyde

Pro-oxidants: iron, transferrin, ferritin, blood lipids, Trigliseride, free fatty acid, lipoproteins, Vit C & E

HyperhomocysteinemiaAtherosclerosis risk factor (non pregnant)

Around mildpregnancy with elevated serum homocysteine had risk of preeclampsia (D’Anna, 2004; Hietala, 2001)



CytokinesReleased by vascular endothelium and leukocytes

Over 50 cytokine are elevated in preeclampsia

Interleukin and TNF -

Cascade of markers (C-reactive protein) elevations in preeclampsia

Not sufficiently predictive (Savvidou, 2002)



Placental PeptideThe inflamatory cascade placenta producing peptide markers for prediction of Preeclampsia

Placental peptide:Corticotropin-rh, Chorionic gonadotropin, activin A and inhibin A (Aquilina, 1999; Cuckle 1998)

Activin A and Inhibin A were increased markedly in preeclampsia (keelan and colleagues, 2002)

Activin A and Inhibin A reported significant overlap in normotensive and preeclampsia (Grobman and Wang, 2002)



Fetal DNAIdentification of Fetal DNA in marternal serum prediction of preeclampsia (Zhong, 2001)

Endothelial activation and inflammation occur, fetal cells and cellular material maternal circulation.



Uterine Artery Doppler VelocimetrySecond trimester - uteroplacental vacular resistance (by doppler of uterine artery)

Basic conceptsImpaired trophoblastic invasion of the spiral arteries uteroplacental blood flow descreases

Bower (1993)Sensitivity: 78%




Prevention

Dietary ManipulationSalt restriction ineffective (Knuist, 1998)

Prenatal Ca supplementation significant reduction in Blood Pressure and incidence of preeclampsia (Brucher, 1996)

But, Levin, (1997) 4600 nulliparas calcium and placebo preeclampsia or gestational hypertension incidence was similar in each group.


Low dose aspirin60 mg 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

Prevention (Continued)


AntioxidantsDavidge, 1992

Markedly reduced antioxidant activity in preeclampsia women.

Chappel, 1999283 high risk women

18 - 22 weeks, Vit C and E versus placebo

Significant reduction in preeclampsia (11%-17%)

Prevention (Continued)


Diagnosis

Etiology

Pathogenesis

Pathophysiology


Management

Index

Management

Basic management objective for any pregnancy complicated by preeclamsia are:1. Termination of pregnancy with the least

possible trauma to mother and fetus.

2. Birth an infant who subsequently thrives

3. Complete restoration of health to the mother


ReferensiWilliams Obstetric 22 Edition, Chapter 34: hypertension disorders in pregnancyThe Texbook’s Kidney Disease and Hypertension in Pregnancy, 2003Dewhurst's Textbook of Obstetrics and Gynaecology 7th Edition

Medical Physiology Lippincott Williams and Wilkins, 2nd edition 2004

http://hyper.ahajournals.org, 2002. Pathophysiology of Hypertension During Preeclampsia Linking Placental Ischemia With Endothelial Dysfunction.

The Journal of Clinical Endocrinology & Metabolism, 2003. Endothelial Cells and Peripheral Blood Mononuclear Cells Are a Potential Source of Extraplacental Activin A in Preeclampsia.

VGN-CR11GH

hypertensive disorders in pregnancy (williams 22 edition)

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