Hypertensive Disorders of

Pregnancy
DR. SHAURYA BASAK
PGT, Unit B2
Introduction
1. Hypertensive disorders of pregnancy constitute one of the leading causes
of maternal and perinatal mortality worldwide (16%)
2. It has been estimated that preeclampsia complicates 2–8% of pregnancies
globally
3. In Africa and Asia they contribute to 9% of maternal deaths
Terminology
The Task Force of the ACOG(2013) describes 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
Diagnosis
● Hypertension: BP≥ 140 mm Hg systolic
or 90 mm Hg diastolic
● Delta Hypertension:
○ A sudden rise in MAP but still in a
normal range.
○ Some will develop preeclampsia,or
eclamptic seizures / HELLP
syndrome while still normotensive.
Gestational Hypertension
● BP ≥ 140/90 mm Hg for the first time, on two occasions at least 4 hours
apart, after 20 weeks of gestation in a woman with a previously normal
blood pressure, but in whom proteinuria is not identified.
● Half of these women subsequently develop preeclampsia syndrome,10%
eclamptic seizures develop before overt proteinuria can be detected.
● Gestational hypertension is reclassified by some as transient
hypertension if evidence for preeclampsia does not develop and the
blood pressure returns to normal by 12 weeks postpartum.
Preeclampsia Syndrome
● Preeclampsia is a multisystem disorder of unknown etiology
characterized by development of hypertension ≥ 140/90 mm Hg, with
proteinuria or features of end-organ dysfunction after the 20th week of
gestation in a previously normotensive and nonproteinuric woman
● Preeclampsia is much more than simply gestational hypertension with
proteinuria, but the appearance of proteinuria remains an important
diagnostic criterion
● Proteinuria is an objective marker and reflects the system-wide
endothelial leak that characterizes the preeclampsia syndrome
Preeclampsia Syndrome (Cont.)
The Task Force of the ACOG(2013) suggests the following diagnostic criteria:
Indicators of Severity
Severity of HDP can be classified as: Severe or Nonsevere
Ominous Symptoms
● Preeclampsia when complicated with grandmal seizures and/or coma that
is not attributable to any other cause is called eclampsia.
● Seizures are generalized tonic-clonic convulsions and maybe
antepartum(50%), intrapartum(30%),postpartum(10%) or late postpartum
(10%)
● In 80% cases, preceded by features of severe preeclampsia:
○ Headaches or visual disturbances such as scotomata
○ Epigastric or right upper quadrant pain, due to hepatocellular
necrosis, ischemia, and edema that ostensibly stretches Glisson
capsule
○ Thrombocytopenia represents platelet activation and aggregation as
well as microangiopathic hemolysis
Preeclampsia Superimposed on Chronic Hypertension
● Chronic underlying hypertension: Women with documented blood
pressures >140/90 mm Hg before pregnancy or before 20 weeks
gestation
● Superimposed preeclampsia: If new-onset or worsening baseline
hypertension is accompanied by new-onset proteinuria or other
diagnostic criterias of preeclampsia
● Compared with preeclampsia, superimposed preeclampsia commonly
develops earlier in pregnancy, tends to be more severe is accompanied by
fetal growth restriction.
Risk Factors of Preeclampsia
● Genetic: 5% in white, 9% in Hispanic, and 11% in African-American
● Nulliparous(3-10%, compared to 1.4-4% in multi)
● Prior preeclampsia
● Chronic hypertensives, CVD, CKD
● Diabetes, Obesity
● Multifetal gestation
● BMI > 30
● APLA syndrome, SLE
● ART, Prior abruption, Hyperhomocysteinemia, HIV seropositivity
Etiopathogenesis
Gestational hypertensive disorders are more likely to develop in women who:

● Are exposed to chorionic villi for the first time

● Are exposed to a superabundance of chorionic villi (twins/mole)
● Have preexisting conditions associated with endothelial cell activation or
inflammation(diabetes, obesity, CVD, CKD, immunological disorders)
● Are genetically predisposed to hypertension developing during
pregnancy.
Etiopathogenesis
● The preeclampsia syndrome varies widely in its clinical phenotypic
expression.
● At least two major subtypes are differentiated by whether or not
remodeling of uterine spiral arterioles by endovascular trophoblasts is
defective.
● This concept has given rise to the “two-stage disorder” theory of
preeclampsia pathogenesis: Stage 1 is caused by faulty endovascular
trophoblastic remodeling that downstream causes the stage 2 clinical
syndrome.
● Importantly, stage 2 can be modified by preexisting maternal conditions
that are also manifest by endothelial cell activation or inflammation and
are listed in the third prior bullet.
Etiology
Currently considered mechanisms to explain the cause of preeclampsia are:

1. Abnormal trophoblastic invasion of uterine vessels

2. Immunological maladaptive tolerance between maternal, 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.
Etiology(Cont.)
1. Abnormal trophoblastic invasion of uterine vessels:
● Normally there is invasion of the endovascular
trophoblasts into the walls of the the spiral arterioles of
the uteroplacental bed.
● In10–12 weeks, invasion up to decidual segments and
in 16–18 weeks another wave of invasion up to the
myometrial segments occurs.
● This process replaces the endothelial lining and the
muscular arterial wall by fibrinoid formation.
● This physiological change transforms the spiral
arterioles into a low resistance, low pressure, high flow
system
● In preeclampsia, there is failure of the second wave of
endovascular trophoblast migration and there is
reduction of blood supply to the fetoplacental unit
Etiology(Cont.)
2. Immunological factors:

● Survival of the semiallogenic fetal graft requires complex interactions

between fetal trophoblasts and maternal decidual immune cells.
● Loss of Maternal immune tolerance to paternally derived placental and
fetal antigens
● Explains the elevated risk :
○ When there is two sets of paternal chromosomes(molar pregnancies)
○ Women with a trisomy 13 (as the gene for SFLT1 is on chr 13)
○ First pregnancy ( women previously exposed to paternal antigens are
“immunized” )
Etiology(Cont.)
3. Endothelial cell activation:

● In response to ischemia or other inciting causes, placental factors are

released and begin a cascade of events that leads to oxidative stress
● Antiangiogenic and metabolic factors and other inflammatory leukocyte
mediators are thought to provoke systemic endothelial cell injury
● Cytokines such as TNF-α and the ILs may contribute to the systemic
oxidative stress
Etiology(Cont.) Production of the lipid-laden macrophage foam
cells seen in placental atherosis
3. Endothelial cell activation:
Systemic oxidative stress Activation of systemic microvascular
coagulation manifested by
thrombocytopenia
ROS and free radicals

Greater systemic capillary permeability

Formation of self-propagating lipid peroxides reflected by edema and proteinuria

Generation of highly toxic radicals

● Injure systemic vascular endothelial cells

● Modify nitric oxide production
● Interfere with prostaglandin balance
Etiology(Cont.)
4. Genetic factors:

Ward and Taylor (2015):

● 20 to 40 percent for daughters of preeclamptic mothers

● 11 to 37 percent for sisters of preeclamptic women
● 22 to 47 percent for twins.

Ethnoracial factors are important, as evidenced by the high incidence of preeclampsia in

African-American women.

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.Thus, the clinical manifestation in any given woman with
the preeclampsia syndrome will occupy a spectrum. I
Etiology(Cont.)
4. Genetic factors:
Pathogenesis
1. Vasospasm:

● Systemic endothelial activation causes vasospasm that elevates resistance

to produce subsequent hypertension.
● Systemic endothelial cell injury promotes interstitial leakage, and blood
constituents are deposited subendothelially.
● Endothelial junctional proteins are also disrupted, and the subendothelial
region of resistance arteries undergoes ultrastructural change
● With diminished blood flow because of vasospasm and interstitial
leakage, ischemia of the surrounding tissues can lead to necrosis,
hemorrhage, and other end-organ disturbances
Pathogenesis(Cont.)
2. Endothelial cell injury:

● Protein factors, likely placental,are secreted into the maternal circulation

and provoke activation and dysfunction of the systemic vascular
endothelium
● Intact endothelium has anticoagulant properties. Also, systemic
endothelial cells, by releasing nitric oxide, blunt the response of vascular
smooth muscle to agonists.
● Injured or activated endothelial cells may produce less nitric oxide and
may secrete substances that promote coagulation and greater sensitivity
to vasopressors
Pathogenesis(Cont.)
3. Increased pressor responses:
● Pregnant women normally develop refractoriness to infused vasopressors
● Women with early preeclampsia, however, have enhanced vascular reactivity to
infused norepinephrine and angiotensin II

● Several prostaglandins are thought to be central to preeclampsia syndrome

pathophysiology because the blunted pressor response seen in normal
pregnancy is at least partially due to diminished vascular responsiveness
mediated by endothelial prostaglandin synthesis
● Endothelial prostacyclin (PGI2 ) production is lower in preeclampsia and the
prostacyclin:thromboxane A2 ratio declines. The net result favors greater
sensitivity to infused angiotensin II and, ultimately, vasoconstriction
Pathogenesis(Cont.)
3. Increased pressor responses:

● Nitric oxide is a potent vasodilator synthesized from L-arginine by endothelial cells.

● Inhibition of nitric oxide synthesis raises mean arterial pressure, lowers heart rate, and
reverses the pregnancy-induced refractoriness to vasopressors
● Preeclampsia is associated with decreased endothelial nitric oxide synthase
expression, thus resulting in lower nitric oxide activity

● Endothelins are 21-amino-acid peptides and potent vasoconstrictors.

● Plasma ET-1 levels are elevated in normotensive pregnant women, but women with
preeclampsia have even higher levels.
● Interestingly, treatment of preeclamptic women with magnesium sulfate lowers ET-1
concentrations
Pathogenesis(Cont.)
4. Angiogenic and Antiangiogenic Proteins:

● Placental vasculogenesis is evident by 21 days after conception.

● The list of proand antiangiogenic substances involved in placental
vascular development is extensive, and the families of vascular
endothelial growth factor (VEGF) and angiopoietin are the most studied.
● Angiogenic imbalance describes excessive amounts of antiangiogenic
factors, which are thought to be stimulated by worsening hypoxia at the
uteroplacental interface.
Pathogenesis(Cont.)
4. Angiogenic and Antiangiogenic Proteins:
● Trophoblast of women destined to develop preeclampsia overproduces at
least two antiangiogenic peptides that enter the maternal circulation:
sFLT1 and sEng
Pathophysiology
Cardiovascular System:
Cardiovascular disturbances are related to:
(1) greater cardiac afterload caused by hypertension
(2) cardiac preload, which is reduced by a pathologically diminished volume
expansion during pregnancy and which is increased by intravenous crystalloid
or oncotic solutions
(3) endothelial activation leading to interendothelial extravasation of
intravascular fluid into the extracellular space and, importantly, into the lungs.
Pathophysiology(Cont.)
Myocardial function:
● Serial echocardiographic studies document diastolic dysfunction in 40 to
45 percent
● Diastolic dysfunction stems from ventricular remodeling, which is judged
to be an adaptive response to maintain normal contractility despite the
increased afterload of preeclampsia. High levels of antiangiogenic
proteins may be contributory
● In the otherwise healthy pregnant woman, these changes are usually
clinically inconsequential. But when combined with underlying ventricular
dysfunction, further diastolic dysfunction may cause cardiogenic
pulmonary edema
Pathophysiology(Cont.)
Ventricular function:
● Clinical cardiac function in most preeclamptic women is appropriate.
● In some preeclamptic women, cardiac troponin levels are slightly elevated, and
Nt pro-BNP levels are elevated with severe preeclampsia
● Both normally pregnant women and those with preeclampsia syndrome can
have normal or slightly hyperdynamic ventricular function and cardiac output
that is appropriate for left-sided filling pressures.
● Thus, aggressive hydration results in overtly hyperdynamic ventricular function.
This is accompanied by elevated pulmonary capillary wedge pressures, and
pulmonary edema may develop despite normal ventricular function. This is
because of an alveolar endothelial-epithelial leak, and it is compounded by
decreased oncotic pressure from a low serum albumin concentration
Pathophysiology(Cont.)
Blood Volume:

● Hemoconcentration is a hallmark of eclampsia

● Such hemoconcentration results from generalized vasospasm that follows
endothelial activation and leakage of plasma into the interstitial space
● Women of average size have a blood volume of 3000 mL, and during the
last several weeks of a normal pregnancy, this averages 4500 mL. With
eclampsia, however, much or all of the anticipated 1500 mL excess is lost.
● Women with severe hemoconcentration are unduly sensitive to blood loss
at delivery that otherwise may be considered normal
Pathophysiology(Cont.)
Thrombocytopenia:
● Decreased platelet concentrations with eclampsia were described more than
100 years ago.
● The frequency and intensity of thrombocytopenia vary and are dependent on
the severity and duration of the preeclampsia syndrome
● Overt thrombocytopenia (platelet count <100,000/μL) indicates severe disease
● In most cases, delivery is advisable because worsening thrombocytopenia
usually ensues. After delivery, the platelet count may continue to decline for the
first day or so. It then usually rises progressively to reach a normal level within 3
to 5 days
● Abnormally low platelets do not develop in the fetuses or neonates born to
preeclamptic women despite severe maternal thrombocytopenia
Pathophysiology(Cont.)
Hemolysis:
● Severe preeclampsia is frequently accompanied by hemolysis, which
manifests as elevated serum lactate dehydrogenase levels and reduced
haptoglobin levels.
● Other evidence comes from schizocytosis, spherocytosis, and
reticulocytosis in peripheral blood.
● These derangements result in part from microangiopathic hemolysis
caused by endothelial disruption with platelet adherence and fibrin
deposition and in part from serum lipid alterations. Related, substantively
decreased long-chain fatty acid content is found in erythrocytes of
preeclamptic women
Pathophysiology(Cont.)
Coagulation changes:
● Elevated factor VIII consumption, increased levels of fibrinopeptides A and
B and of D-dimers
● Reduced levels of regulatory proteins(antithrombin III and proteins C and
S).
● Coagulation aberrations generally are mild and are seldom clinically
significant
● Unless placental abruption is comorbid, plasma fibrinogen levels do not
differ remarkably
● Routine laboratory assessments of coagulation profile are not required in
the management of pregnancy-associated hypertensive disorders.
Pathophysiology(Cont.)
Endocrine and Hormonal Alterations:

● Plasma levels of renin, angiotensin II, angiotensin 1–7, aldosterone,

deoxycorticosterone, and atrial natriuretic peptide (ANP) are substantively
augmented during normal pregnancy.
● ANP is released during atrial wall stretching from blood volume
expansion, and it responds to cardiac contractility
● Levels of serum ANP rise in pregnancy, and its secretion is further
enhanced in women with preeclampsia. Levels of its precursor(proatrial
natriuretic peptide)are also increased in preeclampsia
● Vasopressin levels are similar
Pathophysiology(Cont.)
Fluid shift:

● In women with severe preeclampsia, the volume of extracellular fluid,

manifest as edema, is usually much greater than that in normal pregnant
women.
● The mechanism responsible is endothelial injury.
● These women have reduced plasma oncotic pressure. This reduction
creates a filtration imbalance and further displaces intravascular fluid into
the surrounding interstitium.
Pathophysiology(Cont.)
Electrolyte altercations:

● Electrolyte concentrations do not differ appreciably in women with

preeclampsia compared with those of normal pregnant women.
● Following an 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
Pathophysiology(Cont.)
Kidney:
● During normal pregnancy, renal blood flow and glomerular filtration rate
rise appreciably
● In preeclampsia, renal perfusion and glomerular filtration are reduced
● Most of the decrement in glomerular filtration is from higher renal
afferent arteriolar resistance that may be elevated up to fivefold
● Morphological changes are characterized by glomerular endotheliosis,
which blocks the barrier that allows filtration. Diminished filtration causes
serum creatinine levels to rise
● In most preeclamptic women, the urine sodium concentration is elevated.
Urine osmolality rises, urine:plasma creatinine ratio is elevated, and
fractional excretion of sodium is low
Pathophysiology(Cont.)
Kidney:

● Sodium-containing crystalloid infusion raises left ventricular filling

pressure, and rapid infusions may cause clinically apparent pulmonary
edema
● Plasma uric acid concentration is typically elevated in preeclampsia. The
elevation exceeds that attributable to the reduction in glomerular
filtration rate and likely is also due to enhanced tubular reabsorption
● Preeclampsia is associated with diminished urinary excretion of calcium,
perhaps because of greater tubular reabsorption
Pathophysiology(Cont.)
Kidney:
● Clinically apparent acute tubular
necrosis is almost invariably induced
by comorbid hemorrhage with
hypovolemia and hypotension
● In one review of women with HELLP
syndrome, 5 percent had kidney
injury (Haddad, 2000). Of those with
renal injury, half had placental
abruption, and most had postpartum
hemorrhage.
● Last, irreversible renal cortical
necrosis develops rarely
Pathophysiology(Cont.)
Liver:
● The characteristic hepatic lesions with eclampsia are regions of periportal
hemorrhage in the liver periphery
● Liver involvement with preeclampsia may clinically display at least three
manifestations:
○ First, pain is considered a sign of severe disease. It typically manifests by moderate-to-severe
right upper quadrant or midepigastric pain and tenderness. In some cases, however, the amount
of hepatic tissue involved with infarction may be surprisingly extensive yet still clinically
insignificant.Infarction may be worsened by hypotension from obstetrical hemorrhage, and it
occasionally causes hepatic failure—also called shock liver
○ Second, elevations of serum AST and ALT levels are markers for severe preeclampsia. Values
seldom exceed 500 U/L, but levels reaching more than 2000 U/L have been reported.
○ As a third presentation, hemorrhagic infarction may extend to form a hepatic hematoma. This
in turn can extend to form a subcapsular hematoma that may rupture. CT or MRI greatly aids
diagnosis . Current management of a hepatic hematoma usually consists of observation unless
bleeding is ongoing. In some cases, however, prompt surgical intervention or angiographic
embolization may be lifesaving.
Pathophysiology(Cont.)
HELLP:
● This is an acronym for Hemolysis (H), Elevated Liver enzymes (EL) and Low
Platelet count (LP) .
● This is a rare complication of preeclampsia (10–15%). HELLP syndrome
may develop even without maternal hypertension.
● This syndrome is manifested by nausea, vomiting, epigastric or right
upper quadrant pain, along with biochemical, and hematological changes.
● Complications: Eclampsia(6%), Placental abruption(10 %), AKI (5%), and
pulmonary edema(10%). Stroke, hepatic hematoma, coagulopathy, acute
respiratory distress syndrome, and sepsis were other serious
complications.
Pathophysiology(Cont.)
HELLP:
● In the Tennessee Classification System diagnostic criteria for HELLP are
haemolysis with increased LDH (> 600 U/L), AST (≥ 70 U/L), and platelets <
100 x 109/L.
● The Mississippi Triple-class HELLP System further classifies the disorder
by the nadir platelet counts:
○ 1: Platelets ≤ 50x 109/L, AST or ALT ≥ 70 IU/L, LDH ≥ 600 IU/L
○ 2: Platelets ≤ 100x 109/L but ≥ 50x 109/L, AST or ALT ≥ 70 IU/L, LDH ≥
600 IU/L
○ 3: Platelets ≤ 150x 109/L but ≥ 100x 109/L, AST or ALT ≥ 40 IU/L, LDH ≥
600 IU/L
Pathophysiology(Cont.)
Findings in Acute Liver Diseases in Pregnancy:
Pathophysiology(Cont.)
Brain:

● Neuroimaging studies show:

○ Hypodense areas in the cortex
○ Cerebral edema
○ Capillary thrombosis
○ Infarction
○ Intraventricular and parenchymal hemorrhages
○ Necrosis
● Clinical manifestations of headache, scotomata, blindness, convulsions
are due to PRES(Posterior reversible encephalopathy syndrome)
Pathophysiology(Cont.)
PRES:
● Posterior (Occipital and Posterior Parietal Lobes) Reversible Encephalopathy
Syndrome (PRES) is a transient neuroradiological entity characterized by the
features of hypertension, generalized seizures, altered mental status, headache
and vision changes.
● The hallmark of diagnosis is bilateral symmetrical vasogenic edema in the
occipital and posterior parietal lobes evident on T2-weighted MRI
● Underlying pathology is thought to be cerebral edema, and vasospasm of
cerebral and retinal vessels.
● PRES is usually reversible with prompt diagnosis and treatment. Rarely it may
lead to cortical infarction and irreversible ischemic damage and even death.
● Neuroradiologic imaging should be done in a patient with persistant headache,
hypertension, seizures or visual changes (blindness) even in the postpartum
period
Pathophysiology(Cont.)
Uteroplacental Perfusion:
● There is increased evidences of premature aging of the placenta. Areas of
occasional acute red infarcts and white infarcts are visible on the maternal
surface of the placenta.
● Villi: Syncitial degeneration, increased syncitial knots, marked proliferation of
cytotrophoblast, thickening of the basement layer, and proliferative endarteritis
are evident in varying degrees.
● In preeclampsia, the musculoelastic media in the myometrial segment remains
responsive to vasoconstrictor stimuli resulting in decreased blood flow.
● There is acute atherosis of spiral arteries with obliteration of lumen.
● Intervillous circulation: The blood flow is impaired to the extent of about
one-third, secondary to the changes in the maternal blood vessels. This results
in placental changes, anatomical and functional, which are responsible for fetal
jeopardy.
Pathophysiology(Cont.)
Uteroplacental Perfusion:
● Measurement of uterine artery blood flow velocity has been used to
estimate resistance to uteroplacental blood flow. Vascular resistance is
estimated by comparing arterial systolic and diastolic velocity waveforms.
● Studies were done to assess this by measuring peak systolic:diastolic
velocity ratios from uterine and umbilical arteries in preeclamptic
pregnancies. In some cases, but certainly not all, there was higher
resistance.
● Another Doppler waveform—uterine artery “notching”—has been
associated with elevated risks for preeclampsia or fetal-growth restriction
especially in early onset disease
Prediction
Various biological markers implicated in the preeclampsia syndrome have been
measured to help predict its development.
Although most have been evaluated in the first half of pregnancy, some have been
tested as predictors of severity in the third trimester
The tests are related to assessing:
● Vascular Resistance Testing and Placental Perfusion
● Fetal-Placental Unit Endocrine Function
● Renal Function Tests
● Endothelial Dysfunction and Oxidant Stress
● Others
Overall, these efforts have resulted in testing strategies with poor sensitivity and
with poor positive-predictive values for preeclampsia. Currently, no screening
tests for preeclampsia are predictably reliable, valid, and economical.
Prediction(Cont.)
Vascular Resistance Testing and Placental Perfusion:
● Roll-over test:At 28 to 32 weeks’ gestation, woman rests in the left
lateral decubitus position and then roll to the supine position.
Increased blood pressure with this maneuver signifies a positive test.
● The isometric exercise test: Employs the same principle by squeezing a
handball.
● The angiotensin II infusion test: Performed by giving incrementally
increasing doses intravenously, and the hypertensive response is
quantified.

Sensitivities of all three tests were reported to range from 55 to 70 percent,

and specificities approximated 85 percent.
Prediction(Cont.)
Vascular Resistance Testing and Placental Perfusion:
● Uterine artery Doppler velocimetry is posited to reflect faulty
trophoblastic invasion of the spiral arteries. This failure results in
diminished placental perfusion and upstream greater uterine artery
resistance.
● Increased uterine artery velocimetry determined by Doppler
ultrasound in the first two trimesters might provide indirect evidence of
this process and thus serve as a predictive test for preeclampsia
● Elevated flow resistance results in an abnormal vessel waveform
represented by an exaggerated diastolic notch.
These findings have value for prediction of fetal-growth restriction but
not preeclampsia
Prediction(Cont.)
Fetal-Placental Unit Endocrine Function:
Several serum analytes have been proposed to help predict preeclampsia:
● hCG
● AFP
● Estriol
● PAPP-A
● Inhibin A,
● Activin A
● Placental protein 13
● Procalcitonin
● Corticotropin releasing hormone
● A disintegrin
● ADAM-12
● Kisseptin
Prediction(Cont.)
Renal Function Tests:
● Hyperuricemia likely results from reduced uric acid clearance
from diminished glomerular filtration, increased tubular
reabsorption, and decreased secretion. Sensitivity: 0 to 55
percent, and specificity was 77 to 95 percent.
● Isolated gestational proteinuria is a risk factor for preeclampsia
Microalbuminuria has sensitivities that range from 7 to 90 percent
and specificities that span 29 to 97 percent
● Others: Urinary calcium, kallikrein, microtransferrinuria,
podocyturia, podocalyxin, N-acetyl-β-glucosaminidase, cystatin C
Prediction(Cont.)
Endothelial Dysfunction and Oxidant Stress :
● Fibronectins are high-molecular-weight glycoproteins released from endothelial cells
and extracellular matrix following endothelial injury
● Thrombocytopenia and platelet dysfunction are integral features of preeclampsia.
Platelet activation causes augmented destruction and lower concentrations
● Higher levels of lipid peroxides coupled with decreased antioxidant activity
● Others: Iron, transferrin, and ferritin; resistin; hyperhomocysteinemia; blood lipids,
including triglycerides, free fatty acids, and lipoproteins; and antioxidants such as
ascorbic acid and vitamin E
● Serum levels of VEGF and PlGF begin to drop before clinical preeclampsia develops.
Levels of some antiangiogenic factors, such as sFlt-1 and sEng, begin to rise
Sensitivities for all cases of preeclampsia ranged from 30 to 50 percent, and specificity
approximated 90 percent. Their predictive accuracy is higher for early-onset preeclampsia
Determination of the sFlt-1/PlGF ratio in women admitted near 37 weeks’ gestation to
exclude preeclampsia was useful as a predictive factor
Prediction(Cont.)
Others:
● Cell-free DNA (cfDNA) can be detected in maternal plasma. It is
hypothesized that cfDNA is released in preeclampsia by
accelerated apoptosis of cytotrophoblasts
● Others: AT-3, ANP, β2 microglobulin, haptoglobin, 25-OH Vit D,
hepatic aminotransferases, and urine and serum proteomic,
metabolomic, and transcriptomic technologies.
Prevention
Various strategies used to prevent or modify preeclampsia severity
have been evaluated below. In general, none of these has been found
to be convincingly and reproducibly effective.
● Regular antenatal check up (early detection of rapid gain in weight
or a tendency of rising blood pressure)
● Dietary and Lifestyle Modifications
● Antihypertensive Drugs
● Antioxidants
● Antithrombotic Agents
Prevention(Cont.)
Dietary and Lifestyle Modifications:
● A low-salt diet was one of the earliest research efforts to prevent
preeclampsia but a randomized trial showed that a
sodium-restricted diet was ineffective in preventing preeclampsia
(Knuist, 1998)
● Regular exercise during pregnancy is linked to a lower risk of
developing preeclampsia (Barakat, 2016; Morris, 2017)
● Most trials have shown that unless women are calcium deficient,
calcium supplementation has no salutary effects.
● Fish oil supplementation have shown no benefits in randomised
trials
Prevention(Cont.)
Antihypertensive drugs:
● In one metaanalysis of nine randomized trials with more than
7000 pregnancies, women given diuretics had a lower incidence of
edema and hypertension but not of preeclampsia (Churchill,
2007).
● Because women with chronic hypertension are at high risk for
preeclampsia, several randomized trials have evaluated various
antihypertensive drugs to reduce the incidence of superimposed
preeclampsia . A critical analysis of these trials by Staff and
coworkers (2015) failed to demonstrate benefits for this goal.
Prevention(Cont.)
Antioxidants:

● The Combined Antioxidant and Preeclampsia Prediction Studies (CAPPS) by

the MFMU Network included almost 10,000 low-risk nulliparas (Roberts,
2010). None of these studies showed reduced preeclampsia rates in women
provided vitamins C and E compared with those given placebo.
● Statins were proposed to prevent preeclampsia because they stimulate
hemoxygenase-1 expression, which inhibits sFlt-1 release. Preliminary animal
data suggest that statins may prevent hypertensive disorders of pregnancy
● Metformin inhibits hypoxic inducible factor 1α by lowering mitochondrial
electron transport chain activity. It reduces sFlt-1 and sEng activity and thus has
potential to prevent preeclampsia
Prevention(Cont.)
Antithrombotic agents:
● Rodger and colleagues (2016) performed a metaanalysis using
individual patient data from 963 women on LMWH. The risk for
recurrent preeclampsia, abruption, or fetal-growth restriction was
similar in women receiving heparin or placebo.
● Aspirin, in low oral doses of 50 to 150 mg daily, effectively inhibits
platelet thromboxane A2 biosynthesis but has minimal effects on
vascular prostacyclin production (Wallenburg, 1986). Still, several
clinical trials have shown limited benefits in preeclampsia
prevention
Prevention(Cont.)
Antithrombotic agents:

● From recent metaanalyses, it is found that low-dose aspirin(81mg/day)

prophylaxis initiated before 16 weeks’ gestation was associated with a 10-60%
risk reduction for preeclampsia and fetal-growth restriction
Management of Preeclampsia
Initial evaluation:

● A complete blood count with platelet estimate, serum creatinine,

LDH, AST, ALT, and testing for proteinuria should be obtained in
parallel with a comprehensive clinical maternal and fetal evaluation
● In the evaluation of possible preeclampsia superimposed upon
chronic hypertension, a uric acid test may be considered
● Fetal evaluation should include ultrasonographic evaluation for
estimated fetal weight and amount of amniotic fluid, as well as fetal
antepartum testing
Delivery vs. Expectant Management
Conditions Precluding Expectant Management:

● Maternal
○ Uncontrolled severe-range blood pressures
○ Persistent headaches, refractory to treatment
○ Epigastric pain or right upper pain unresponsive to repeat analgesics
○ Visual disturbances, motor deficit or altered sensorium
○ Stroke
○ Myocardial infarction
○ HELLP syndrome
○ New or worsening renal dysfunction
○ Pulmonary edema
○ Eclampsia
○ Suspected acute placental abruption or vaginal bleeding in the absence of placenta previa
● Fetal
○ Abnormal fetal testing
○ Fetal death
○ Fetus without expectation for survival at the time of maternal diagnosis (eg, lethal anomaly,
extreme prematurity)
○ Persistent reversed end-diastolic flow in the umbilical artery
Delivery vs. Expectant Management (Cont.)
A. Preterm gestation with GH or non-severe PE:
● Continued observation is appropriate mode of management
● Delivery is recommended at 37 0/7 weeks of gestation in the absence of
abnormal antepartum testing, preterm labor,PPROM or vaginal bleeding,
for neonatal benefit
● Serial USG to determine fetal growth, weekly antepartum testing, close
monitoring of blood pressure, and weekly laboratory tests for
preeclampsia needs to be done
● The frequency of these tests may be modified based on clinical findings
and patient symptoms.
● Following the initial documentation of proteinuria and the establishment of
the diagnosis of preeclampsia, additional quantifications of proteinuria are
no longer necessary.
Delivery vs. Expectant Management (Cont.)
A. Preterm gestation with GH or non-severe PE:
● Women should be advised to immediately report any persistent,
concerning, or unusual symptoms.
● In women with gestational hypertension without severe features,
progression to preeclampsia with severe features usually takes 1–3 weeks,
whereas in women with preeclampsia without severe features, the
progression to severe preeclampsia could happen within days.
● So, delivery is recommended when gestational hypertension or preeclampsia
with severe features is diagnosed at or beyond 34 0/7 weeks of gestation,
after maternal stabilization or with labor or prelabor rupture of
membranes
● Delivery should not be delayed for the administration of steroids in the late
preterm period
Delivery vs. Expectant Management (Cont.)
B. Severe PE before 34 weeks:
● In women with stable maternal and fetal condition, expectant management may
be considered
● Close maternal and fetal clinical monitoring is necessary, and laboratory testing
(complete blood count including platelets, liver enzymes, and serum creatinine,
urine protein:creatinine ratio) should be performed at least every 2 days
● During expectant management, delivery is recommended at any time in the case of
deterioration of maternal or fetal condition
● If delivery is indicated at less than 34 0/7 weeks of gestation, administration of
corticosteroids for fetal lung maturation is recommended but delaying delivery
for optimal corticosteroid exposure is not advisable
● Previously, fetal growth restriction was considered an indication for delivery. In
the setting of normal fetal parameters (eg, amniotic fluid volume, Doppler
findings, antenatal fetal testing), continuation of expectant management may be
done
Delivery vs. Expectant Management (Cont.)
B. Severe PE before 34 weeks:
● Delay Delivery if possible for Corticosteroid induced lung maturation:
○ Preterm ruptured membranes or labor
○ Thrombocytopenia <100,000/μL
○ Hepatic transaminase levels twice upper limit of normal
○ Fetal-growth restriction
○ Oligohydramnios
○ Reversed end-diastolic Doppler flow in umbilical artery
○ Worsening renal dysfunction
● Don’t delay delivery:
○ Uncontrolled severe hypertension
○ Eclampsia
○ Pulmonary edema
○ Placental abruption
○ Disseminated intravascular coagulation
○ Nonreassuring fetal status Fetal demise
Inpatient vs. Outpatient Management
● Ambulatory management at home is an option only for women with
gestational hypertension or preeclampsia without severe features and
requires frequent fetal and maternal evaluation
● Hospitalization is appropriate for women with severe features and for
women in whom adherence to frequent monitoring is a concern.
● Fetal monitoring consists of ultrasonography to determine fetal growth
every 3–4 weeks of gestation and amniotic fluid volume assessment at
least once weekly
● An antenatal test one-to-two times per week for patients with gestational
hypertension or preeclampsia without severe features is recommended
● Maternal evaluation consists primarily of frequent evaluation for either the
development of or worsening of preeclampsia. In women with gestational
hypertension or preeclampsia without severe features, weekly evaluation
of platelet count, serum creatinine, and liver enzyme levels is
recommended. In addition, for women with gestational hypertension, once
weekly assessment of proteinuria is recommended.
Intrapartum Seizure Prophylaxis
● The rate of seizures in preeclampsia with severe features without
magnesium sulfate prophylaxis is four times higher than in those
without severe features (4 in 200 versus 1 in 200)
● It has been calculated that 129 women need to be treated to prevent
one case of eclampsia in asymptomatic cases, whereas in
symptomatic cases the number needed to treat is 36
● Magnesium sulfate is more effective than phenytoin, diazepam, or
nimodipine in reducing eclampsia and should be considered the drug
of choice in the prevention of eclampsia in the intrapartum and
postpartum periods
● Benzodiazepines and phenytoin are justified only in the context of
antiepileptic treatment or when magnesium sulfate is
contraindicated or unavailable (myasthenia gravis, hypocalcemia,
moderate-to-severe renal failure, cardiac ischemia, heart block, or
myocarditis).
Intrapartum Seizure Prophylaxis (Cont.)
● There are still sparse data regarding the ideal dosage of magnesium
sulfate. Even the therapeutic range of 4.8– 9.6 mg/dL (4–8 mEq/L)
quoted in the literature is questionable
● Seizures occur even with magnesium at a therapeutic level, whereas
several trials using infusion rates of 1 g/hour, frequently associated
with subtherapeutic magnesium levels, were able to significantly
reduce the rate of eclampsia or recurrent convulsions
● Further complicating aspects are that steady magnesium levels are
reached more slowly during the antepartum period than postpartum
period
● It has been reported in patients with a high BMI (especially greater
than 35) that the antepartum level of magnesium may remain
subtherapeutic for as long as 18 hours after infusion initiation
Intrapartum Seizure Prophylaxis (Cont.)
Regimens for Magnesium Sulphate:
Intrapartum Seizure Prophylaxis (Cont.)
● For women requiring cesarean delivery (before onset of labor), the infusion
should ideally begin before surgery and continue during surgery, as well as
for 24 hours afterwards. For women who deliver vaginally, the infusion
should continue for 24 hours after delivery
● Magnesium sulfate has significant anesthetic implications because it
prolongs the duration of nondepolarizing muscle relaxants. However,
women with preeclampsia who require cesarean delivery should continue
magnesium sulfate infusion during the delivery because magnesium
sulfate half-life is 5 hours and discontinuation of the infusion of
magnesium sulfate before cesarean delivery would only minimally reduce
magnesium concentration at the time of delivery while possibly increasing
the risk of seizure
● The rate of adverse effects is higher with the intramuscular administration.
The adverse effects of magnesium sulfate (respiratory depression and
cardiac arrest) come largely from its action as a smooth muscle relaxant.
Intrapartum Seizure Prophylaxis (Cont.)

● The serum concentration of magnesium is related to the occurrence

of adverse effects and toxicities
● Patients at risk of impending respiratory depression may require
tracheal intubation and emergency correction with calcium gluconate
10% solution, 10 mL IV over 3 minutes, along with furosemide
intravenously to accelerate the rate of urinary excretion
Intrapartum Seizure Prophylaxis (Cont.)
● Because magnesium sulfate is excreted almost exclusively in the urine,
measuring urine output should be part of the clinical monitoring, in
addition to monitoring of respiration status and tendon reflexes.
● The initial 4-g loading dose of magnesium sulfate can be safely
administered regardless of renal function.
● In patients with mild renal failure (serum creatinine 1.0–1.5 mg/dL) or
oliguria (less than 30 mL/ hour for more than 4 hours), the loading dose of
4–6 g should be followed by a maintenance dose of only 1 gm/hour
● In cases with renal dysfunction, laboratory determination of serum
magnesium levels every 4 hours becomes necessary. If the serum level
exceeds 8 mEq/L, the infusion should be stopped and serum magnesium
levels should be determined at 2-hour intervals and can be restarted at a
lower rate when the serum level decreases to less than 7 mEq/L
Antihypertensives
● The objectives of treating severe hypertension are to prevent
congestive heart failure, myocardial ischemia, renal injury or failure,
and ischemic or hemorrhagic stroke.
● Antihypertensive treatment should be initiated expeditiously for
acute-onset severe hypertension (systolic blood pressure of 160 mm
Hg or more or diastolic blood pressure of 110 mm Hg or more, or
both) that is confirmed as persistent (15 minutes or more)
● Intravenous hydralazine or labetalol and oral nifedipine are the three
agents most commonly used for this purpose
● Although parenteral antihypertensive therapy may be needed initially
for acute control of blood pressure, oral medications can be used as
expectant management is continued. Oral labetalol and calcium
channel blockers have been commonly used
Antihypertensives (Cont.)
● One approach is to begin an initial regimen of labetalol at 200 mg orally every 12 hours
and increase the dose up to 800 mg orally every 8–12 hours as needed (maximum total
2,400 mg/ d). If the maximum dose is inadequate to achieve the desired blood pressure
goal, or the dosage is limited by adverse effect, then short-acting oral nifedipine can be
added gradually
Mode of Delivery
● The mode of delivery in women with gestational hypertension or
preeclampsia (with or without severe features) should be determined
by routine obstetric considerations
● For gestational hypertension or preeclampsia without severe
features, vaginal delivery is preferred
● Retrospective studies comparing induction of labor with cesarean
delivery in women with preeclampsia with severe features remote
from term concluded that induction of labor was reasonable and was
not harmful to low-birth-weight infants
● The decision to perform cesarean delivery should be individualized,
based on anticipated probability of vaginal delivery and on the nature
and progression of preeclampsia disease state
Anaesthesia Considerations
● With improved techniques over the past decades, regional anesthesia
has become the preferred technique for women with preeclampsia
with severe features and eclampsia for labor and delivery
● General anesthesia carries more risk to pregnant women than
regional anesthesia does because of the risk of aspiration, failed
intubation because of pharyngolaryngeal edema, and stroke
secondary to increased systemic and intracranial pressures during
intubation and extubation
● However, neuraxial anesthesia and analgesia are contraindicated in
the presence of a coagulopathy because of the potential for
hemorrhagic complications
● Thrombocytopenia also increases the risk of epidural hematoma but
the risk of epidural hematoma from neuraxial anesthetics in a
parturient patient with a platelet count of more than 70x10 9/L is
exceptionally low (less than 0.2%)
Complications of Eclampsia
● Major maternal complications:
○ Placental abruption (10%)
○ Neurological deficits (7%)
○ Aspiration pneumonia (7%)
○ Pulmonary edema (5%)
○ Cardiopulmonary arrest (4%)
○ Acute renal failure (4%)
○ Death (1%)
● Because of maternal hypoxemia and lactic acidemia caused by
convulsions, fetal bradycardia often follows a seizure . The fetal heart
rate usually recovers within 2 to 10 minutes. If it persists more than
about 10 minutes, another cause of bradycardia, such as placental
abruption or imminent delivery, should be considered
Clinical features of Eclampsia
● Eclamptic seizures may be violent, and the woman must be protected,
especially her airway. So forceful are the muscular movements that the
woman may throw herself out of her bed, and if not protected, her
tongue is bitten by the violent action of the jaws. This phase, in which the
muscles alternately contract and relax, may last approximately a minute.
Gradually, the muscular movements become smaller and less frequent,
and finally the woman lies motionless
● After a seizure, the woman is postictal, but in some, a coma of variable
duration ensues. When the convulsions are infrequent, the woman usually
recovers some degree of consciousness after each attack.
● As the woman arouses, a semiconscious combative state may ensue.
● As a rule, however, death does not occur until after frequent convulsions.
● Finally and also rarely, convulsions may continue unabated—status
epilepticus—and require deep sedation and even general anesthesia to
obviate anoxic encephalopathy
Clinical features of Eclampsia (Cont.)
● Respiratory rate >50/min in response to hypercarbia, lactic acidemia, and
transient hypoxia. Cyanosis may be observed in severe cases.
● High fever is a grave sign (Cerebrovascular hemorrhage)
● Proteinuria usually present
● Urine output may be diminished appreciably, and occasionally anuria
develops. There may be hemoglobinuria, but hemoglobinemia is rare.
● Facial and peripheral edema
● Pulmonary edema is usually caused by aspiration pneumonitis. In some
women, pulmonary edema may be caused by ventricular failure from
increased afterload that results from severe hypertension.
● Occasionally, sudden death occurs synchronously with an eclamptic
convulsionand ost often in these cases, a massive cerebral hemorrhage is
the cause
● Hemiplegia may result from sublethal hemorrhage.
● Blindness with severe preeclampsia without convulsions is due to retinal
detachment. Blindness with eclampsia is due to occipital lobe edema
Management of Eclampsia
● The initial steps in the management of a woman with eclampsia are basic
supportive measures such as calling for help, prevention of maternal injury,
placement in lateral decubitus position, prevention of aspiration, administration
of oxygen, and monitoring vital signs including oxygen saturation
● The main principle of management are:
○ Control of convulsions using an intravenously administered loading dose of
magnesium sulfate that is followed by a maintenance dose, usually
intravenous, of magnesium sulfate
○ Intermittent administration of an antihypertensive medication to lower
blood pressure whenever it is considered dangerously high
○ Avoidance of diuretics unless pulmonary edema is obvious, limitation of
intravenous fluid administration unless fluid loss is excessive, and
avoidance of hyperosmotic agents
○ Delivery of the fetus to resolve preeclampsia (after stabilisation of mother)
Management of Eclampsia (Cont.)
● Cochrane reviews, including data originating from developing
countries, indicate a significant reduction in recurrent seizures and
eclampsia-related maternal mortality with the use of magnesium
sulfate.
● Magnesium sulfate administered intramuscularly or intravenously is
superior to phenytoin, diazepam, or lytic cocktail (usually
chlorpromazine, promethazine, and pethidine) and also is associated
with less maternal and neonatal morbidity
● In the rare cases of an extremely agitated patient, IV clonazepam 1
mg, diazepam 10 mg, or midazolam may be used for sedation to
facilitate the placement of the IV lines and Foley catheter, and the
collection of blood specimens.
Management of Eclampsia (Cont.)
● It has been proposed that when convulsions recur, a further 2–4
grams of magnesium sulfate could be administered IV over 5 minutes
● In cases refractory to magnesium sulfate (still seizing at 20 minutes
after the bolus or more than two recurrences), a health care provider
can use sodium amobarbital (250 mg IV in 3 minutes), thiopental, or
phenytoin (1,250 mg IV at a rate of 50 mg/minute)
● Endotracheal intubation and assisted ventilation in the intensive care
unit are appropriate in the circumstances. Head imaging should also
be considered because most of cases refractory to magnesium
sulfate therapy may prove to have abnormal findings on brain
imaging
Management of Eclampsia (Cont.)
● Women with eclampsia should be delivered in a timely fashion.
● However, eclampsia by itself is not an indication for cesarean
delivery.
● Once the patient is stabilized, the method of delivery should depend,
in part, on factors such as gestational age, fetal presentation, and the
findings of the cervical examination.
● A high rate of failure may be anticipated with induction or
augmentation in pregnancies less than 30 weeks of gestation if the
patient is not in active labor and the Bishop score is unfavorable. In
these cases, it may be preferable to opt for cesarean delivery without
further delay
● However, patients that adequately progress in labor could be allowed
to continue labor even after an eclamptic seizure
HDP and CVD
● Women with a history of preeclampsia continue to have an elevated
risk of cardiovascular disease in subsequent years.
● Several systematic reviews and metaanalyses have linked
preeclampsia with an increased risk of cardiovascular disease
(hypertension, myocardial infarction, congestive heart failure),
cerebrovascular events (stroke), peripheral arterial disease, and
cardiovascular mortality later in life, with an estimated doubling of
odds compared with women unaffected by preeclampsia
● Meta-regression analysis reveals a graded relationship between the
severity of preeclampsia or eclampsia and the risk of cardiac disease
● The risk is even higher (4-8 times) in women with recurrent
preeclampsia and women with early onset preeclampsia or
preeclampsia requiring preterm delivery
HDP and CVD (Cont.)
● More recent evidence suggests that all hypertensive conditions in
pregnancy are associated with later cardiovascular disease with an
approximately doubling of the rate of incident cardiovascular disease
and a five times higher rate of hypertension
● The mechanisms that account for an increased risk of cardiovascular
disease in women with a history of preeclampsia are not yet well
understood, but endothelial dysfunction, which has been linked to
atherosclerosis, persists in women with a history of preeclampsia
many years after an affected pregnancy
● It may also be possible that the stress incurred to the cardiovascular
system during gestation triggers a biological response that would
otherwise not have occurred despite any genetic predisposition or
risk factors
HDP and CVD (Cont.)
● It remains unclear if cardiovascular changes associated with preeclampsia
during pregnancy causally lead to cardiovascular remodeling increasing the
risk of cardiovascular disease later in life or if preeclampsia is a
manifestation of an underlying increased risk of cardiovascular disease
● For example, a common genetic–environmental risk factor(s) interaction
[such as hyperlipidemia, obesity, diabetes mellitus, or renal disease] that
predisposes women to develop both preeclampsia during pregnancy and
cardiovascular diseases later in life
● Preventive strategies to be considered by patients and health care
providers may warrant closer long-term follow-up and lifestyle
modifications to better manage risk factors for cardiovascular disease (eg,
achieving healthful weight, exercise, diet, smoking cessation), for which
women and their primary care providers may maintain ongoing care and
vigilance
Thank you