Hypertensive Disorders in Pregnancy (Williams 22 Edition)

Hypertensive Disorders in Pregnancy
Index
Diagnosis
Etiology
Pathogenesis Pathophysiology Prediction and Prevention Management
INTRODUCTION
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
Williams Obstetric 22 edition, Chapter 34: Hypertensive Disorders in Pregnancy
Index
Diagnosis Etiology Pathogenesis Pathophysiology Prediction and Prevention Management
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: a multisystem disorder
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
Preeclampsia
Diastolic hypertension 95mmHg
Increase fetal death rate (38000 prenancy in 1976)
Worsening proteinuria
Increasing preterm delivery Neonatal survival was not significantly altered.
Epigastric or RUQ pain

Hepatocelular necrosis, ischemia, edema that stretches the Glisson capsure AST / ALT elevated sign Hepatic rupture: rare
Thrombocytopenia
Severe vasospasm Microangiopathic hemolysis Platelet activation, aggregation
Pathophysiology
Preeclampsia
The Texbooks Kidney Disease and Hypertension in Pregnancy, 2003
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.
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) Obesity Atrterial abnormalities
Renovascular hypertension Coarcta tion of the aorta
Endocrinedisorders
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

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
Nulliparous
Total:7.6% and severe: 3.3% (Hauth, 2000)
Risk factor
Chronic hypertension, multifetal gestation, maternal old age (>35 yrs), obesity, AfricanAmerican ethnicity
Incidence and Risk Factor

Maternal weight and the risk of preeclampsia is progressive. BMI (Kg/m2) <19.8
>35
Morbidity (%) 4.3

13.3 13 5
Gestation twin single
(Sibai, 2000)
Smoking during pregnancy reduced risk of hypertension during pregnancy (Bainbridge,2005 ; Zhang, 1999) Placenta previa also reduced the risk of hypertension
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
Index
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
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
Abnormal Trophoblastic Invasion

In Preeclamsia
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
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

SEL ENDOTHEL
OH- radikal
H 2 O2
Peroksida lipid
MEMBRANE
NUKLEUS
PROTEIN
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 preeclampsia C-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 daughtersin-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)
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 Vasospasm
Vasocontriction spiral arteries Failure of Cytotrophoblast invasion of the spiral arteries
The Complication of Vasospasm
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
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
Platelets
Index
Pathophysiology Vascular Changes in Pregnancy
Dewhurst's Textbook of Obstetrics and Gynaecology 7th Edition
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

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.
Severe Preeclamsia and Eclampsia: Associated Hemodynamic Measurements
Ventricular Function in Severe Preeclampsia-Eclampsia
(Hankin, 1984)
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. Depending on severity, hemoconcentration is usually not as marked. Whereas, gestational hypertension have a normal blood volume (Silver, 1998)
Comparing nonpregnant Mean Blood Volume
Blood and Coagulation

Platelet
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 Homeostasis Endocrine changes
Volume Homeostasis Endocrine changes

Deoxycorticosterone (DOC)
Another potent mineralocorticoid Increses 3rd trimester
Result 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.
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)
Liver
Periportal hemorrhagic necrosis in the periphery of the liver lobule
Serum liver enzyme is elevated Hepatic rupture (more rare), subcapsular hematoma (more common). Treatment
Surgical intervention may be life saving Blood 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 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 Theraphy - controversial

Differential Diagnosis of Microangipathic Syndrome During Pregnancy
Brain
Common Subjectif
Headache, visual disturbance - associated convulsion (eclampsia)
Anatomical pathology
Gross hemorrhage - severe hypertension
These complications in women with underlying chronic hypertension
Postmortem cerebral lesion

Edema, hyperemia, focal anemia, thrombosis, hemorrhage.
Brain
Neuroimaging study
CT
All women with eclampsia have abnormal brain finding Hypodense cotical area petechial hemorrhage and infarction site (at autopsy)
MRI
Described remarkable changes in the posterior Cerebral artery area. 25% of women with eclampsia have areas of cerebral infarction
Magnetic Resonance Imaging
MRIs performed 6 weeks after delivery complicated by eclampsia
Brain
Cerebral Blood Flow
Eclampsia loss of autoregulation of cerebral blood flow (Apollon, 2000)
Hyperperfusion similar in hypertensive encephalopathy.
Increased cerebral perfusion headache.
Brain
Blindness 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

Brain
Cerebral Edema
Subjectif
Letharge, confusion, blurred vision to obtundation and, coma
Mental status change correlated with brain involvement seen with CT and MRI studies Sudden severe blood pressure elevatoins
Vasogenic edema Blood pressure control.
Electroencephalopgraphy
Reported 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
Measurement
Spiral artery 500m (normal), 200 m (preeclampsia) Placental blood flow
Inaccesibility, 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
Index
Prediction and Prevention

Prediction
Lots of attemption to predict preeclampsia in early pregnancy poor sensitivity, poor positive predictive value
Prediction (Continued)
Roll over test
Hypertensive 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)
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)

16 weeks - 20 weeks, 378 low-risk nulliparas Positive predictive value: 29% Negative predictive value: 98%
Oxidative Stress
Lipid peroxides level increases descreases antioxidants activity preeclampsia prediction (Walsh, 1994) Marker
Lipid peroxides: malondialdehyde Pro-oxidants: iron, transferrin, ferritin, blood lipids, Trigliseride, free fatty acid, lipoproteins, Vit C & E
Hyperhomocysteinemia
Atherosclerosis risk factor (non pregnant) Around mildpregnancy with elevated serum homocysteine had risk of preeclampsia (DAnna, 2004;
Hietala, 2001)
Cytokines
Released 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 Peptide
The 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 DNA
Identification 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 Velocimetry
Second trimester - uteroplacental vacular resistance (by doppler of uterine artery) Basic concepts
Impaired trophoblastic invasion of the spiral arteries uteroplacental blood flow descreases
Bower (1993)
Sensitivity: 78% Positive predictive value: 28%
Prevention
Dietary Manipulation
Salt 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.
Prevention (Continued)
Low dose aspirin
60 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)
Antioxidants
Davidge, 1992
Markedly reduced antioxidant activity in preeclampsia women.
Chappel, 1999
283 high risk women 18 - 22 weeks, Vit C and E versus placebo Significant reduction in preeclampsia (11%-17%)
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
Referensi
Williams Obstetric 22 Edition, Chapter 34: hypertension disorders in pregnancy The Texbooks Kidney Disease and Hypertension in Pregnancy, 2003 Dewhurst'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.

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Hypertensive Disorders in Pregnancy

Superimposed preeclamsia (on chronic hypertension)

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

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

Pre-eclampsia: a multisystem disorder

Increased certainty of preeclampsia

Epigastric or RUQ pain

The Texbooks Kidney Disease and Hypertension in Pregnancy, 2003

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

Indications of Severity of Hypertensive Disorder during Pregnancy

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

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

Underlying Causes of Chronic hypertensive Disorder

Glomerulonephritis (acute and chronic) Renoprival hypertension

Connetive tissue disease

Polycystic kidney disease Acute renal failure

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

Preeclampsia Superimposed on Chronic Hypertension

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

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

Incidence and Risk Factor

Incidence and Risk Factor

Morbidity (%) 4.3

Gestation twin single

Incidence and Risk Factor (Eclampsia)

1976 (williams Obstetrics 15th edition)

2000, National Vital Statistics Report, in US

1994, Douglas and Redman in UK

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

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

Physiology Cythotrophoblast Invasion

The Texbooks Kidney Disease and Hypertension in Pregnancy, 2003

Invasion Cytotrophoblast Cells

The Texbooks Kidney Disease and Hypertension in Pregnancy, 2003

Abnormal Trophoblastic Invasion

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

Normal placental implantation shows proliferation of extravillous trophoblasts

Abnormal Trophoblastic Invasion

Using Electron Micorscopy

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

ISKEMIC PLACENTA O2 O2 radical

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

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

Vasospam Spiral Arteries

The Texbooks Kidney Disease and Hypertension in Pregnancy, 2003

The Texbooks Kidney Disease and Hypertension in Pregnancy, 2003

The Complication of Vasospasm

The Texbooks Kidney Disease and Hypertension in Pregnancy, 2003

Damaged or activated endothelial cells secrete substances

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

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

Increased Pressor Responses

Pathophysiology Vascular Changes in Pregnancy

Dewhurst's Textbook of Obstetrics and Gynaecology 7th Edition

Extravasion into the extracellular space, especially the lung

With clinical onset of preeclampsia

By contrast, Gestational hypertension

Severe Preeclamsia and Eclampsia: Associated Hemodynamic Measurements

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

Ventricular Function in Severe Preeclampsia-Eclampsia

Comparing nonpregnant Mean Blood Volume

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

Blood and Coagulation

Volume Homeostasis Endocrine changes