HYPERTENSIVE DISORDERS

Four types of hypertensive disease:

1. Preeclampsia and eclampsia syndrome
2. Chronic hypertension of any etiology
3. Preeclampsia superimposed on chronic hypertension
4. Gestational hypertension-definitive evidence for the preeclampsia syndrome does not develop and hypertension resolves by 1 2 weeks
postpartum.
Diagnosis of Hypertensive Disorders
 blood pressure exceeds 1 40 mm Hg systolic or 90 mmHg diastolic.
 BEFORE: increases 30 mmHg systolic or 15 mmHg diastolic at midpregnancy when BP values were <140/90 mmHg
o observed closely, eclamptic seizures develop in some
"Delta Hypertension"
 sudden rise in mean arterial pressure still in a normal range
 Some will have preeclampsia
 Some even develop eclamptic seizures or HELLP (hemolysis, elevated liver enzyme levels, low platelet count) syndrome while still
normotensive
Gestational Hypertension
 BP 140/90 mm Hg or greater for the first time after mid pregnancy, but proteinuria is not identified.
 10% of eclamptic seizures develop before overt proteinuria
 transient hypertension- evidence for preeclampsia does not develop and the blood pressure returns to normal by
12 weeks postpartum
Preeclampsia Syndrome
 pregnancy-specific syndrome affecting every organ system
 gestational hypertension with proteinuria
 proteinuria
o objective marker
o reflects the system-wide endothelial leak
 preeclampsia syndrome, neither overt proteinuria nor fetal-growth restriction are features

Indicators of Preeclampsia Severity

 Some symptoms are considered ominous

 Headaches or visual disturbances (scotomata) precede eclampsia
o Generalized Seizures may appear before, during, after labor
o 10% 48hr postpartum
 epigastric or right upper quadrant pain
o hepatocellular necrosis, ischemia, and edema that stretches Glisson capsule
 o elevated serum hepatic transaminase levels
 thrombocytopenia
o platelet activation and aggregation as well as microangiopathic hemolysis.
 Other factors indicative of severe preeclampsia
o renal or cardiac involvement
o obvious fetal-growth restriction
o early-onset disease
 more profound, the less likely they can be temporized, and the more likely that delivery will be required.
 A caveat is that differentiation between non severe and severe gestational hypertension or preeclampsia can be misleading because what
might be apparently mild disease may progress rapidly to severe disease.
Preeclampsia Superimposed on Chronic Hypertension
 Chronic hypertensive disorder predisposes a woman to develop superimposed preeclampsia syndrome
 Chronic hypertension is diagnosed with blood pressures > 140/90 mmHg before pregnancy or before 20 weeks' gestation, or both
 Difficult problems with diagnosis and management who are not first seen until after mid-pregnancy
o 2nd and early 3rd tri, BP normally drops
o 3rd tri, BP returns, difficult to determine whether chronic or induced by pregnancy
 Some with chronic HPN, BP rises to abnormal levels after 24 weeks' gestation.
 If accompanied by new-onset proteinuria or other findings, superimposed preeclampsia is diagnosed.
 Superimposed preeclampsia
o develops earlier in pregnancy
o more severe
o more often accompanied by fetal-growth restriction
INCIDENCE AND RISK FACTORS
 Young and nulliparous women are particularly vulnerable to developing preeclampsia
 Older women are at greater risk for chronic hypertension with superimposed preeclampsia

 the metabolic syndrome and hyperhomocysteinemia

 Pregnancies with a male fetus at slightly higher risk
 smoking during pregnancy carries a reduced risk for hypertension
 Other factors: (HIV) seropositivity and sleep-disordered breathing
ETIOPATHOGENESIS
 Gestational hypertensive disorders are more likely to develop in women with the following characteristics:
o exposed to chorionic villi for the first time
o exposed to a superabundance of chorionic villi (twins or hydatidiform mole)
o preexisting conditions associated with endothelial cell activation or inflammation (diabetes, obesity, cardiovascular or renal
disease, immunological disorders, or hereditary influences)
o genetically predisposed to hypertension developing during pregnancy.
 A fetus is not a requisite for preeclampsia to develop.
o Chorionic villi are essential, need not be intrauterine.
 Cascade of events leading to the preeclampsia syndrome is characterized by abnormalities that result in systemic vascular endothelial
damage with resultant vasospasm, transudation of plasma, and ischemic and thrombotic sequelae.
Phenotypic Expression of Preeclampsia Syndrome
 2 major subtypes differentiated by whether or not remodeling of uterine spiral arterioles by endovascular trophoblasts is defective
 "two-stage disorder"
 stage 1
o faulty endovascular trophoblastic remodeling that downstream causes the stage 2 clinical syndrome
  stage 2
o systemic inflammatory response
o can be modified by preexisting maternal conditions
ETIOLOGY
Currently considered important include:
1. Placental implantation with abnormal trophoblastic invasion of uterine vessels
2. Immunological maladaptive tolerance between maternal, paternal (placental), and fetal tissues
3. Maternal maladaptation to cardiovascular or inflammatory changes of normal pregnancy
4. Genetic factors including inherited predisposing genes and epigenetic influences
1. Abnormal Trophoblastic Invasion
- normal implantation
o characterized by extensive remodeling of the spiral arterioles within the decidua basalis
o Endovascular trophoblasts replace the vascular endothelial and muscular linings to enlarge the vessel diameter
o The veins are invaded only superficially.
- Preeclampsia
o trophoblastic invasion may be incomplete
o decidual vessels become lined with endovascular trophoblasts
o deeper myometrial arterioles do not lose their endothelial lining and musculoelastic tissue, and their mean external diameter is only half
that of corresponding vessels in normal placentas
o lower levels of soluble antiangiogenic growth factors may be involved in this faulty endovascular remodeling
- Placental electron microscopy studies, early preeclamptic changes include endothelial damage, insudation of plasma constituents into vessel
walls, proliferation of myointimal cells and medial necrosis
- Atherosis-lipid accumulation in myointimal cells and macrophages
o common in placentas with preeclampsia before 34 weeks
o may identify those at greater risk for atherosclerosis and cardiovascular disease
- Abnormally narrow lumen of spiral arterioles likely impairs placental blood flow.
o Diminished perfusion and a hypoxic environment eventually lead to release of placental debris or microparticles.
- At this point, these changes incite a systemic inflammatory response, which is stage 2 of the preeclampsia syndrome
- Defective placentation is posited to further cause the susceptible woman to develop
o gestational hypertension
o the preeclampsia syndrome
o preterm delivery
o a growth-restricted fetus
o placental abruption
2. Immunological Factors
- Loss of maternal immune tolerance to paternally derived placental and fetal antigens
- Histological changes at the maternal-placental interface are suggestive of acute graft rejection
- Preeclampsia is an immune-mediated disorder
o enhanced in impaired formation of blocking antibodies to placental antigenic sites
o First pregnancy would carry a higher risk
o Elevated risk when the paternal antigenic load is increased (two sets of paternal chromosomes-a "double dose) - Tolerance
dysregulation
 molar pregnancies (early-onset preeclampsia)
 trisomy 13 fetus (30-40% incidence of preeclampsia)
 elevated serum levels of antiangiogenic factors.
 solubleins-like tyrosine kinase 1 (chrom13)
o Women previously exposed to paternal antigens, such as a prior pregnancy with the same partner
 "immunized"
 not as apparent in women with a prior abortion
o Multiparas impregnated by a new consort have a greater risk of preeclampsia
- Immune maladaptation
o extravillous trophoblasts early in pregnancy express reduced amounts of immunosuppressive non classic human leukocyte antigen G
(HLA G)
 contribute to defective placental vascularization in stage 1 of the preeclampsia syndrome
o Normal pregnancy: type 2 activity is increased in (humoral immunity)
 women with preeclampsia (early 2ND tri)
 Th 1 action is increased (stimulate inflammatory cytoine secretion)
3. Endothelial Cell Activation
- Inflammatory changes are believed to be a continuation of stage 1 alterations
- Placental factors released and begin a cascade of events (response to ischemia/ other inciting cause)
- Antiangiogenic and metabolic factors and other inflammatory leukocyte mediators are thought to provoke systemic endothelial cell injury
=endothelial cell activation or dysfunction.
 - Endothelial cell dysfunction
o Ext-Activated state of leukocytes in maternal circulation
o (TNF-a) and the interleukins may contribute to the systemic oxidative stress associated with preeclampsia
 ROS and free radicals  self-propagating lipid peroxide 
 (1) generate highly toxic radicals that injure systemic vascular endothelial cells
 (2) modify nitric oxide production
 (3) interfere with prostaglandin balance
 Other consequences of oxidative stress: production of the lipid-laden macrophage foam cells (placental atherosis), activation of
systemic microvascular coagulation (thrombocytopenia), and greater systemic capillary permeability (edema and proteinuria).
4. Genetic Factors
- Preeclampsia appears to be a multifactorial, polygenic disorder
- incident risk for preeclampsia
o 20 to 40 percent for daughters of preeclamptic mothers;
o 11 to 37 percent for sisters of preeclamptic women;
o 22 to 47 percent for twins.
- The hereditary predisposition for preeclampsia likely stems from interactions of literally hundreds of inherited genes both maternal and
paternal-that control myriad enzymatic and metabolic functions throughout every organ system
PATHOGENESIS
1. Vasospasm
 Systemic endothelial activation vasospasm elevates resistance hypertension.
 Systemic endothelial cell injury: interstitial leakage and blood constituents (platelets and fibrinogen) deposited subendothelially
 Endothelial junctional proteins disrupted subendothelial region of resistance arteries undergoes ultrastructural change.
 With diminished blood flow because of maldistribution from vasospasm and interstitial leakage, ischemia of the surrounding tissues
can lead to necrosis, hemorrhage, and other end-organ disturbances characteristic of the syndrome.
 One important clinical correlate to this is the markedly attenuated blood volume seen in women with severe preeclampsia

2. Endothelial Cell Injury

 Injury to systemic endothelial cells is now a centerpiece of preeclampsia pathogenesis
 protein factor(s)-likely placental-are secreted into the maternal circulation and provoke activation and dysfunction of the systemic
vascular endothelium
 Intact endothelium
 Anticoagulant properties
 Releases NO to blunt the response of vascular smooth muscle to agonists.
 Injured or activated endothelial cells
 produce less NO
 secrete substances that promote coagulation and greater sensitivity to vasopressors
- Further evidence of endothelial activation includes the characteristic changes in glomerular capillary endothelial morphology, greater
capillary permeability, and elevated blood concentrations of substances associated with endothelial activation.
3. Increased Pressor Responses
- pregnant women normally develop refractoriness to infused vasopressor
- Women with early preeclampsia, however,have enhanced vascular reactivity to infused norepinephrine and angiotensin II
- Several prostaglandins
o normal pregnancy: diminished vascular responsiveness mediated by endothelial prostaglandin synthesis.
o Preeclampsia: endothelial prostacyclin (PGI2) production is lower
 phospholipase A2
 thromboxane A2 (plt) increased and the prostacyclin:thromboxane A2 ratio declines. Net
 favors greater sensitivity to infused angiotensin II and, ultimately, vasoconstriction
- Nitric oxide
o decreased endothelial nitric oxide
synthase expression, thus resulting in lower nitric oxide activity
- Endothelins are 21 -amino-acid peptides and potent vasoconstrictors produced by human edothelium
o Plasma ET- 1 levels are elevated in normotensive pregnant women
o women with preeclampsia have even higher levels likely arise from systemic endothelial activation
o treatment of preeclamptic women with magnesium sulfate lowers ET- 1 concentrations animal studies
o sildenafil reduces ET- 1 concentrations

4. Angiogenic and Antiangiogenic Proteins

- Placental vasculogenesis is evident by 21 days after conception
- Angiogenic imbalance describes excessive amounts of antiangiogenic factors, thought to be stimulated by worsening hypoxia at the
uteroplacental interface.
- Trophoblast of women destined to develop preeclampsia overproduces at least two antiangiogenic peptides that enter the maternal
circulation
- soluble fins-like tyrosine kinase 1 {sFlt-i} is a receptor for VEGF.
 o elevated maternal sFlt- 1 levels inactivate and reduce circulating free placental growth
factor (PIGF) and VEGF concentrations, leading to endothelial dysfunctions
o Flt-1 levels begin to rise in maternal serum months before preeclampsia is evident
o high levels in the second trimester are associated with a doubling of the risk for preeclampsia
- soluble endoglin (sEng),
o inhibits various TGF-B isoforms from binding to endothelial receptors
o Endoglin is one of these receptors
o Decreased binding to endoglin diminishes endothelial nitric oxide-dependent vasodilatation.
o Serum levels of sEng also begin to rise months before clinical preeclampsia develops
o metformin reduces antiangiogenic secretion from human tissues

PATHOPHYSIOLOGY
 Consequence of endothelial dysfunction, vasospasm, and ischemia
Cardiovascular System
 (1) greater cardiac afterload due to HPN;
 (2) cardiac preload reduced by diminished volume expansion increased by crystalloid/oncotic solutions
 (3) endothelial activation leading to interendothelial extravasation of intravascular fluid into the
extracellular space (importantly, into lungs)
Hemodynamic Changes and Cardiac Function
 depends on several modifiers like preeclampsia severity, hypertension severity, presence of underlying chronic disease
 cardiac output declines, due to greater peripheral resistance
 Myocardial Function
o diastolic dysfunction in 40 to 45 percent
o ventricles do not properly relax and cannot fill properly
o ventricular remodeling, adaptive response to maintain normal contractility despite increased afterload
o High levels of antiangiogenic proteins
o No preeclampsia, inconsequential. Unless combined with underlying ventricular dysfunction.
 Ventricular Function
o cardiac troponin levels are slightly elevated, and Nt pro-BNP levels are elevated with severe preeclampsia
o Normal & preeclamptic can have normal or slightly hyperdynamic ventricular function. Thus, cardiac output is appropriate for filling
pressures.
o Filling pressures depends on volume of IV fluids. Thus, aggressive hydration hyperdynamic ventricular function with PCWP and
pulmonary edema
o Due to alveolar endothelial-epithelial leak + decreased oncotic pressure (low albumin)
o In sum, aggressive fluid administration to normal women with severe preeclampsia substantially elevates normal left sided filling
pressures and raises a physiologically normal cardiac output to hyperdynamic levels
Blood Volume
 Hemoconcentration is a hallmark of eclampsia.
 Normally pregnant: blood volume of 3000 mL then during last several weeks of a pregnancy ~4500 mL
 In eclampsia, 1500 mL excess is lost from endothelial activation and leakage of plasma into the interstitial space vasospasm
hemoconcentration
 Preeclampsia, hemoconcentration not marked.
 Severe hemoconcentration: sensitive to blood loss at delivery (~normal)
 After delivery, vasospasm & plasma leakage persists as endothelium restored to normal.
 Vasoconstriction reverses BV reexpands   hct
 Substantive cause of this fall in hematocrit is usually blood loss incurred at delivery.
 Anemia may also partially result from greater erythrocyte destruction.
Maternal Thrombocytopenia
 Overt thrombocytopenia-defined by a platelet count < 1 00,000 -indicates severe disease
 the lower the platelet count, the higher the rates of maternal and fetal morbidity and mortality
 Delivery is advisable because worsening thrombocytopenia ensues
 After delivery plt count continue to decline for first day then rises to reach normal in 3 to 5 days.
 with HELLP syndrome, the platelet count continues to fall after delivery. If not normal until 48 to 72 hours, preeclampsia syndrome may
be incorrectly attributed to one of thrombotic microangiopathies
 Myriad of other platelet alterations attributed to the preeclampsia syndrome: platelet activation with increased α-degranulation producing β-
thromboglobulin, factor 4, and enhanced clearance.
 Platelet aggregation is reduced compared with the normal increase of pregnancy.
o "exhaustion" following activation
o immunological processes/ platelet deposition at sites of endothelial damage
 o Platelet-bound and circulating platelet-bindable immunoglobulins elevated suggesting platelet surface alterations.
 Abnormally low platelets do not develop in the fetuses or neonates born to preeclamptic women
 Thus, maternal thrombocytopenia in a hypertensive woman is not a fetal indication or cesarean delivery
Hemolysis
 Severe preeclampsia is frequently accompanied by hemolysis =elevated serum lactate dehydrogenase levels and reduced haptoglobin
levels.
 Other evidence : schizocytosis, spherocytosis, and reticulocytosis in peripheral blood
 These result from microangiopathic hemolysis
caused by endothelial disruption with platelet adherence and fibrin deposition.
 Erythrocyte morphology:serum lipid alterations with substantively decreased longchain fatty acid content
Coagulation Changes
 elevated factor VIII consumption, increased levels of fibrinopeptides A and B and of D-dimers, and reduced levels of regulatory proteins
antithrombin III and proteins C and S.
 Coagulation aberrations: mild and seldom significant
 Unless placental abruption is comorbid, plasma fibrinogen levels do not differ remarkably
 Fibrin degradation products: D-dimers are minimally elevated. As preeclampsia worsens, so do abnormal findings with
thromboelastography
 Routine laboratory assessments of coagulation (PT), (aPTT), and plasma fibrinogen level, are not required
Endocrine and Hormonal Alterations
 Plasma levels of renin, angiotensin II, angiotensin 1-, aldosterone, deoxycorticosterone, and ANP are augmented during normal pregnancy
 ANP released during atrial wall stretching from blood volume expansion, and it responds to cardiac contractility
 Levels of serum ANP and its precursor proatrial natriuretic peptide enhanced in women with preeclampsia
 Vasopressin levels are similar in nonpregnant, normally pregnant, and preeclamptic women even though the metabolic clearance is elevated
in the latter two
Fluid and Electrolyte Alterations
 Severe preeclampsia: extracellular fluid, manifest as edema, much greater than in normal pregnant women.
 Pathological fluid retention is due to endothelial injury
 They have reduced plasma oncotic pressure filtration imbalance & further displaces IVF into interstitium.
 Electrolyte concentrations do not differ in women with preeclampsia compared with normal pregnant women.
 Following eclamptic convulsion, the serum pH and bicarbonate concentration are lowered due to lactic acidosis and compensatory
respiratory loss of carbon dioxide.
 The intensity of acidosis relates to the amount of lactic acid produced (metabolic acidosis) and the rate at which carbon dioxide is exhaled
(respiratory acidosis)
Kidney
 During normal pregnancy, renal blood flow and glomerular filtration rate rise.
 Preeclampsia: Renal perfusion & GFR are reduced.
o Levels less than nonpregnant are infrequent and are consequence of severe disease.
o Reduced GFR is from higher renal afferent arteriolar resistance (5x)
o Morphologic changes: glomerular endotheliosis, blocks barrier that allows filtration.
o Diminished filtration   serum creatinine (nonpregnant =1 mg/mL or higher)
o Begin to normalize 10 days or later after delivery
 Preeclamptic, urine sodium concentration elevated.
o Urine osmolality rises, urine: plasma creatinine ratio is elevated, and fractional excretion of sodium is low (prerenal mechanism)
o Sodium-containing crystalloid infusion raises left ventricular filling pressure= oliguria improves but may cause pulmonary edema.
o Intensive IVF therapy not indicated as "treatment" for preeclamptic women with oliguria unless urine output is diminished from
hemorrhage or fluid loss from vomiting or fever.
 Plasma uric acid concentration elevated in
o attributable to the reduction in glomerular filtration rate and likely is also due to enhanced tubular reabsorption
 Diminished urinary excretion of calcium,
o greater tubular reabsorption
Proteinuria
 Abnormal protein excretion is empirically defined by
o 24-hour urinary excretion >300 mg
o urine protein:creatinine ratio >0.3
o persistent protein values of 30 mg/dL (1 + dipstick) in random urine samples
 For a 24-hour quantitative specimen
o threshold value used is >300 mg/24 h.
o 165 mg in 12-hour sample shows equivalent efficacy
 Urinary protein:creatinine ratio
 o supplant the cumbersome 24-hr quantification
o clean-catch and catheterized urine
o Urine protein:creatinine ratios below 130-150 mg/g, (0.13-0.15) indicate low likelihood of proteinuria exceeding 300 mg/d
o Ratios <0.08 or > 1 .19 have negative- or positive-predictive values of 86 and 96 percent, respectively
o Midrange ratios, 300 mg/g o r 0.3, have poor sensitivity and specificity. Thus, many recommend 24-hour protein excretion should be
quantified.
 With urine dipstick assessment,
o notorious for false-positive &-negative results
 Proteinuria may develop late (already delivered or had an eclamptic convulsion before it appears)
o 10 -15% with HELLP syndrome do not have proteinuria at presentation
o 17 percent of eclamptic women did not have proteinuria by the time of seizures
Anatomical Changes
 Glomeruli are enlarged by ~20%
o "bloodless," & capillary loops variably are dilated and contracted.
 Endothelial cells swollen=glomerular capillary endotheliosis
o lock or partially block the capillary lumens
 Homogeneous subendothelial deposits of proteins and fibrin-like material are seen.
 Endothelial swelling
o Due to angiogenic protein "withdrawal" caused by complexing of free angiogenic proteins with circulating antiangiogenic protein
receptor
o angiogenic proteins are crucial for podocyte health, their inactivation leads to podocyte dysfunction and endothelial swelling.
o eclampsia is characterized by greater excretion of these epithelial podocytes
Acute Kidney Injury
 mild degrees of acute kidney injury are encountered,
 acute tubular necrosis is induced by comorbid hemorrhage with hypovolemia and hypotension
 usually caused by severe obstetrical bleeding-especially placental abruption-coupled with inadequate blood replacement.
 Women with preeclampsia and renal failure
o ½ HELLP syndrome
o 1/3 placental abruption
o Postpartum hemorrhage
o irreversible renal cortical necrosis develops rarely
Liver
 characteristic hepatic lesions with eclampsia are regions of periportal hemorrhage in liver periphery
 some degree of hepatic infarction accompanied hemorrhage in ~ half of women died with eclampsia.
 elevated serum hepatic transaminase levels
 clinically display at least three manifestations
 (1) pain
o sign of severe disease
o moderate-to-severe RUQ or midepigastric pain and tenderness
o usually have elevated (AST) or (ALT) levels.
o In some, infarction may be surprisingly extensive yet still clinically insignificant
o Infarction may be worsened by hypotension from obstetrical hemorrhage, can cause hepatic failure-also called shock liver
 (2) elevations of serum AST and ALT levels are markers for severe preeclampsia.
o seldom exceed 500 U/L (>2000 U/L reported)
o inversely follow platelet levels and normalize within 3 days following delivery
 (3) hemorrhagic infarction
o may extend to form a hepatic hematoma. 
a subcapsular hematomarupture
o CT scanning or MRI imaging aids diagnosis
o Unruptured hematomas common & more likely with HELLP syndrome.
o current management of a hepatic hematoma: observation unless bleeding is ongoing.
o In some cases, prompt surgical intervention or angiographic embolization may be lifesaving.
 Acute fatty liver of pregnancy is sometimes confused with preeclampsia. It too has an onset in late pregnancy, and often accompanying
hypertension, elevated serum transaminase and creatinine levels, and thrombocytopenia. However, the hallmark of acute fatty liver is
significant liver dysfunction.
 Last, no convincing data link pancreatic involvement with preeclampsia syndrome
HELLP Syndrome
 No accepted definition of HELLP syndrome
 Complications included eclampsia (6), placental abruption (10), acute kidney injury (5) and pulmonary edema (10)
 Other serious complications: Stroke, hepatic
hematoma, coagulopathy, acute respiratory distress syndrome, and sepsis
  Women with preeclampsia and HELLP syndrome typically have worse outcomes.
 Eclampsia-15 versus 4 percent; preterm birth-93 versus 78 percent; and perinatal mortality rate-9 versus 4 percent, respectively.
 Postulated that HELLP syndrome has a distinct pathogenesis
Brain
 Headaches and visual symptoms are common with severe preeclampsia, and associated convulsions define eclampsia.

Neuroanatomica l Lesions
 1/3 fatal cases; most deaths due pulmonary edema
 brain lesions were coincidental, gross intracerebral hemorrhage (60%); fatal in only half
 principal lesions: cortical & subcortical petechial hemorrhages.
 classic microscopic vascular lesions: fibrinoid necrosis of the arterial wall and perivascular
microinfarcts and hemorrhages
 Other major lesions include subcortical edema, multiple nonhemorrhagic areas of "sotening" throughout the brain, and hemorrhagic areas
in the white matter. Hemorrhage in the
basal ganglia or pons, sometimes with rupture into the ventricles.
Cerebrovascular Pathophys iology
 Endothelial cell dysfunction that characterizes the preeclampsia syndrome likely in both theories.
 (1) In response to acute and severe hypertension, cerebrovascular overregulation leads to vasospasm. Diminished cerebral blood low
result in ischemia, cytotoxic edema, and eventually tissue infarction.
 (2) Sudden elevations in systemic BP exceed the normal cerebrovascular autoregulatory capacity.
o Regions of forced vasodilation and vasoconstriction in arterial boundary
o Capillary level, disruption of end-capillary pressure causes increased hydrostatic pressure, hyperperfusion, and extravasation of
plasma and red cells through endothelial tight-junction openings leading to vasogenic edema.
 Most likely mechanism is combination of the two.
o Preeclampsia-associated interendothelial cell leak develops at blood pressure (hydraulic) levels much lower than those that usually
cause vasogenic edema and is coupled with a loss of upper-limit autoregulation
 With imaging studies
o posterior reversible encephalopathy syndrome.
o principally involve the posterior brain-the occipital and parietal cortices
o third of cases other areas are involved

N e u rological Man ifestations

 (1) headache and scotomata from cerebrovascular hyperperfusion inoccipital lobes.
o ~75% have headaches, and 20-30% have visual changes before eclamptic convulsions
o mild to severe and intermittent to constant
o do not respond to traditional analgesia, improve after magnesium sulfate infusion.
 (2) Convulsions
o are diagnostic for eclampsia.
o excessive release of excitatory neurotransmitters (Glu) ; massive depolarization of network neurons; and bursts of action potentials
o extended seizures can cause significant brain injury and later brain dysfunction.
 (3) Blindness
o rare with preeclampsia alone
o complicates eclamptic convulsions up to 15%
o may develop a week or more ff delivery
 (4) Generalized cerebral edema
o mental status changes vary from confusion to coma
o dangerous because fatal transtentorial herniation can result
 (5) cognitive decline when studied 5 to 1 0 years following an eclamptic pregnancy
Neuroimaging Studies
 CT imaging, localized hypodense lesions at the gray- and white-matter junction, primarily in the parietooccipital lobes. Also be seen in the
frontal and inferior temporal lobes, the basal ganglia, and
thalamus.
o petechial hemorrhages & local edema.
o Edema of the occipital lobes/ diffuse cerebral edema= blindness, lethargy, and confusion
o Widespread edema= compression or obliteration of the ventricles. Develop signs of life-threatening transtentorial herniation.
 MR imaging
o hyperintense T2 lesions-namely, posterior reversible encephalopathy syndrome (PRES)-in the subcortical and cortical regions of the
parietal and occipital lobes
o Also, the basal ganglia, brainstem, and cerebellum are relatively commonly involved
 o these lesions represent focal cerebral edema.
o PRES lesions with preeclampsia
approximates 20 percent; severe disease and who have neurological symptoms.
o 1/4 hyperintense lesions represent cerebral infarctions that have persistent finding
Visual Changes and Blindness
 Scotomata, blurred vision, or diplopia are common with severe preeclampsia and eclampsia
 improve with magnesium sulfate therapy and/or lowered blood pressure.
 Blindness is less common, reversible, and may arise from visual cortex of the occipital lobe, the lateral geniculate nuclei, and the retina.
 Occipital blindness is also called amaurosis
o affected women usually have evidence of extensive occipital lobe vasogenic edema
o occipital blindness resolves
o Rarely, extensive cerebral infarctions may result in total or partial visual defects.
 Blindness from retinal lesions
o lesions may be ischemia, infarction, or detachment
o SRD/ rarely retinal infarction= Purtscher retinopathy
o SRD is usually unilateral and seldom causes total visual loss.
o asymptomatic SRD is relatively common
 In most cases of eclampsia associated blindness, visual acuity subsequently improves.
 If blindness is caused by retinal artery occlusion, vision may be permanently impaired
Cerebra l Edema
 Symptoms ranged from lethargy, confusion, and blurred vision to obtundation and coma.
 most cases, symptoms waxed and waned.
 Mental status changes correlated with the degree of involvement seen with CT and MR imaging studies
 These women are very susceptible to sudden and severe blood pressure elevations, which can acutely worsen the already widespread
vasogenic edema.
 Thus, careful blood pressure control is essential.
 Consideration is given for treatment with mannitol or dexamethasone
Uteroplacental Perfusion
 Compromised uteroplacental perfusion is almost certainly a major culprit in perinatal morbidity and mortality rates seen with preeclampsia
 Due to defects endovascular trophoblastic invasion
o Measurement of uterine, intervillous, and placental blood flow would be informative.
o inaccessibility of the placenta, the complexity of its venous effluent, and the need for radioisotopes or invasive techniques.
 Uterine artery blood flow velocity has been used to estimate resistance to uteroplacental blood low
o Vascular resistance est: compare arterial systolic and diastolic velocity waveforms.
o By completion of placentation, uterine artery blood flow is decreased, with abnormal placentation, high resistance persists (not all).
 Doppler waveform-uterine artery "notching"
o associated with elevated risks for preeclampsia or fetal-growth restriction
 Resistance in uterine spiral arteries measured
o Impedance was higher in peripheral than in central vessels-a "ring-like" distribution.
o Mean resistance values were greater
 assess placental perfusion ex vivo
o myometrial arteries exhibited endothelium-dependent vasodilatory response.
o others also associated w/ increased resistance
 placental vascularity using a 3D Doppler histogram (placental vasculariy index.)
o Index value was reduced in women with any pregnancy-associated hypertensive disorders.
 Only few women develop compromised uteroplacental circulation
 Preeclampsia in third trimester, only 1/3 with severe disease have abnormal uterine artery velocimetry
 With HELLP syndrome, only a third had abnormal uterine artery waveforms
 In general, the extent of abnormal waveforms correlates with severity of fetal involvement

PREDICTION
 No screening tests or preecampsia are predictaby reliable, valid, and economical. However, combinations of tests, some yet to be
adequately evaluated, may be promising.
Vascular Resistance Testing and Placental Perfusion
 Most tests in this category are cumbersome, time consuming, and overall inaccurate.
 To evaluate blood pressure changes (28-32 AOG)
 (1) roll-over test
o increased blood pressure with this maneuver signifies a positive test.
 (2) isometric exercise test
 o same principle by squeezing a handball.
 (3) angiotensin II infusion test
o giving incrementally increasing doses intravenously, and the hypertensiveresponse is quantified.
 sensitivities (55-70%) and specificities (85%)
 Uterine artey Doppler velocimety
o reflect faulty trophoblastic invasion of spiral arteries
o results in diminished placental perfusion and upstream greater uterine artery resistance.
o Increased uterine artery velocimetry determined by Doppler ultrasound in the first two trimesters might serve as a predictive
test for preeclampsia
 Elevated flow resistance results in an abnormal vessel waveform represented by an exaggerated diastolic notch
o value for prediction of fetal-growth restriction but not preeclampsia
Fetal-Placental Unit Endocrine Function
 Several serum analytes have been proposed
 none of these tests are beneficial for prediction.
Renal Function Tests
 Hyperuricemia likely results from reduced uric acid clearance from diminished glomerular filtration, increased tubular reabsorption, and
decreased secretion.
 sensitivity (0-55%) specificity (77-95%)
 Isolated gestational proteinuria is a risk factor for preeclampsia
 microalbuminuria has sensitivities
(7-90%) and specificities (29-97%)
Endothelial Dysfunction and Oxidant Stress
 (1) Fibronectins are HMW GP released from endothelial cells and ECM ff endothelial injury.
o neither cellular nor total fibronectin levels were clinically useful to predict preeclampsia
 (2) Thrombocytopenia and platelet dysfunction are integral features of preeclampsia.
o Platelet activation augments destruction and lower concentrations.
o Mean platelet volume rises because of platelet immaturity
o Substantive overlap with levels in normotensive pregnant women stultifies their predictive value.
 (3) Markers of oxidative stress
o higher levels of lipid peroxides coupled with decreased antioxidant activity
o iron, transferrin, and ferritin; resistin; hyperhomocysteinemia; blood lipids, including triglycerides, free fatty acids, and lipoproteins;
and antioxidants such as ascorbic acid and vitamin E
o these have not been found to be predictive.
 (4) imbalance in antiangiogenic factors
o serum levels of VEGF and PIGF begin to drop before clinical preeclampsia develops
o sFlt- 1 and sEng, begin to rise
o sensitivities 30-50% and specificity ~90%

o predictive accuracy is higher for early-onset preeclampsia

o Determination of the sFlt- l IPIGF ratio was useful as a predictive factor
o suggest a clinical role for preeclampsia prediction, especially later in pregnancy
o may also predict adverse pregnancy outcomes in women with lupus and comorbid antiphospholipid antibodies
Other Markers
 cell-free DNA (cfDNA) can be detected in maternal plasma & is released in preeclampsia by accelerated apoptosis of cytotrophoblasts
 no correlation between total cfDNA levels and
preeclampsia
 Proteomic, metabolomic, and transcriptomic technologies can be employed to study serum and urinary proteins and cellular metabolites.
PREVENTION
1. Dietary and Lifestyle Modifications
2. Antihypertensive Drugs
3. Antioxidants
4. Antithrombotic Agents

PREECLAMPSIA
 Preeclampsia cannot always be diagnosed definitively
 more frequent prenatal visits if preeclampsia is "suspected”
 Increases in systolic and diastolic blood pressure can be either normal physiological changes or signs of
developing pathology

The basic management objectives for any pregnancy complicated by preeclampsia are:
1. termination of pregnancy with the least possible trauma to mother and fetus
2. birth of a healthy newborn that subsequently thrives
3. complete restoration of health to the mother
 In many women, esp those at or near term, all three objectives are served equally well by induction of labor.
 Most important clinical questions for succesul management is precise knowledge of fetal age.

Early Diagnosis of Preeclampsia

 Women without overt hypertension, but early developing preeclampsia is suspected during routine prenatal
visits are seen more frequenty.
o new-onset diastolic blood pressures > 80 mm Hg but < 90 mm Hg
o sudden abnormal weight gain of more than 2 pounds per week have
o minimum returned for visits at 7 -day intervals
o outpatient surveillance
 Women with overt new-onset hypertension
o either diastolic pressures >90 mm Hg or systolic pressures > 140 mm Hg
o admitted to determine if it is due to pre eclampsia, and if so, to evaluate its severity
Evaluation
 Detailed examination, coupled with daily scrutiny for clinical findings such as headache, visual disturbances,
epigastric pain, and rapid weight gain
 Daily weight measurement
 proteinuria or urine protein:creatinine ratio
o on admittance and at least every 2 days thereafter
 BP readings every 4 hours
 o except between 12 MN and 6 AM unless previous readings are elevated
 plasma or serum creatinine
 hepatic transaminase levels
 hemogram that includes a platelet count
 serum uric acid, lactate dehydrogenase levels,coagulation studies (values has been questioned)
 Evaluation of fetal size and well-being and amnionic fluid volume
o either physical examination or sonography
Activity and nutrition
 Reduced physical activity is likely beneficial, absolute bed rest is not desirable.
 Ample protein and calories are included in the diet
 Sodium and fluid intake are not limited or forced

Consideration for Delivery

 Termination of pregnancy is the only cure or preeclampsia
 Headache, visual disturbances, or epigastric pain
o indicative that convulsions may be imminent
o oliguria is another ominous sign
 Treatment with severe preeclampsia (same with eclampsia)
o anticonvulsant and often antihypertensive therapy, followed by delivery
o forestall convulsions, to prevent intracranial hemorrhage and serious damage to other vital organs, and
to deliver a healthy newborn.
 When the cervix is unfavorable
o Labor induction is carried out, usually with preinduction cervical ripening with a prostaglandin or
osmotic dilator
o Concerns: perceived sense of urgency due to preeclampsia severity, and a need
to coordinate neonatal intensive care
 advocate cesarean delivery
 When the fetus is preterm
o to temporize in the hope that additional weeks in utero will reduce the risk of neonatal death or serious
morbidity from prematurity
o justified in milder cases
 Assessments of fetal well-being and placental function
o nonstress testing or biophysical profile
o Several tests can be used to provide evidence of lung maturity
o An sFlt-l IPlGF ratio <38 is predictive of the short-term absence of preeclampsia
 this ratio testing is still investigational
 women with higher ratios tend to have more adverse outcomes

Hospitalization versus Outpatient Management

 Women with mild-to-moderate stable hypertensionwith or without confirmed preeclampsia
o Monitoring
o reduced physical activity throughout much of the day
o complete bed rest is not recommended
 unachievable because of severe restrictions it places on otherwise well women
 it likely predisposes to thromboembolism
 Many women with mild-tomoderate hypertension are managed at home
o as long as preeclampsia syndrome does not worsen and fetal jeopardy is not suspected
o Sedentary activity throughout the greater part of the day is recommended.
 o These women are instructed in detail to report symptoms.
o Home blood pressure and urine protein monitoring or frequent evaluations by a visiting nurse may
prove beneficial

Antihypertensive Therapy for Mild-to-Moderate Hypertension

 Except for fewer episodes of severe hypertension, none of studies showed any benefits from antihypertensive
treatment
 Hypertensive vs Placebo
o mean pregnancy prolongation, gestational age at delivery, and birthweight did not differ
o cesarean delivery rate and the number of newborns admitted to special-care nurseries
o frequency of growth-restricted neonates was doubled in women given labetalol
Expectant Management of Preterm Severe Preeclampsia
 Aggressive VS expectant management those without HELLP syndrome 28-32 wks (1994)
o Aggressive management included glucocorticoid administration for fetal lung maturation followed by
delivery in 48 hours.
o Expectantly managed women were observed at bed rest and given either labetalol or nifedipine orally
for severe hypertension.
 pregnancy was prolonged for a mean of 15.4 days in the expectant management
 overall improvement in neonatal outcomes was also reported
 expectant management of severe preeclampsia from 24 to 34 weeks(2007)
o placental abruption, HELLP syndrome, pulmonary edema, renal failure, and eclampsia
o perinatal mortality rates averaged 90 per 1 000 births.
o Fetal-growth restriction was common
o Perinatal mortality rates are disproportionately high in these growth-restricted neonate

Expectant Management of Midtrimester Severe Preeclampsia

 Because no neonates survived when delivered before 23 weeks, the Task Force (20 1 3) recommends pregnancy
termination in these case

 Society for MaternalFetal Medicine (20 1 1) has determined that e expectant management is a reasonable
alternative in selected women with severe preeclampsia before 34 weeks (Fig. 40- 1 4). The Task Force (20 1 3)
supports this recommendation.
Corticosteroids to Ameliorate HELLP Syndrome
 No benefits were gained from corticosteroid therapy
 Because of these indings, the 20 13 Task Force does not recommend corticosteroid treatment for
thrombocytopenia with H ELLP syndrome

Experimental therapies