HYPERTENSIVE DISORDERS  Preeclampsia is best described as a pregnancy-specific

syndrome that can affect virtually every organ system. It

 It complicate 5-10% of all pregnancies and they are one of the heralds a higher incidence of cardiovascular disease later in
deadly triad- along with HEMORRHAGE and INFECTION. life.
 Of hypertensive disorders, the PREECLAMPSIA SYNDROME,  Appearance of proteinuria remains an important diagnostic
either alone or superimposed on chronic hypertension, is the criterion. Thus, proteinuria is an objective marker and reflects
most dangerous. the system-wide endothelial leak that characterizes the
 GESTATIONAL HYPERTENSION, defined as the new-onset preeclampsia syndrome.
hypertension during pregnancy, is followed by signs and  The Task Force (2013) suggests other diagnostic criteria
symptoms of preeclampsia almost half the time and (Table 40-1). Evidence of multiorgan involvement may
preeclampsia is identified in 4-5% of all pregnancies. include:
 THROMBOCYTOPENIA
TERMINOLOGY AND DIAGNOSIS  RENAL DYSFUNCTION
 HEPATOCELLULAR NECROSIS
 A Task Force of the American College of Obstetricians and  CENTRAL NERVOUS SYSTEM PERTURBATIONS
Gynecologists (2013) has provided evidence-based  PULMONARY EDEMA
recommendations for clinical practice. The previous basic
classification was retained and describes four types of TABLE 40-1. CLASSIFICATION AND DIAGNOSIS OF
hypertensive disease: PREGNANCY-ASSOCIATED HYPERTENSION
1. PREECLAMPSIA AND ECLAMPSIA SYNDROME CONDITION CRITERIA REQUIRED
2. CHRONIC HYPERTENSION OF ANY ETIOLOGY Gestational Hypertension BP> 140/90 mmHg after 20
3. PREECLAMPSIA SUPERIMPOSED ON CHRONIC weeks in previously
HYPERTENSION normotensive women
4. GESTATIONAL HYPERTENSION- definitive evidence for Preeclampsia: Hypertension plus
the preeclampsia syndrome does not develop and Proteinuria ≥ 300 mg/24 h, or
hypertension resolves by 12 weeks postpartum. Urine protein: creatinine ratio
≥ 0.3, or
 DIAGNOSIS OF HYPERTENSIVE DISORDERS Dipstick 1+ persistent
Thrombocytopenia Platelet count < 100,000/μL
 Hypertension is diagnosed empirically when appropriately
Renal insufficiency Creatinine level >1.1 mg/dl or
taken blood pressure exceeds 140 mmHg systolic or 90
doubling of baseline
mmHg diastolic.
Liver involvement Serum transaminase levels
 Previously, an incremental increase of 30 mmHg systolic or 15
twice normal
mmHg diastolic above blood pressure values taken at
Cerebral symptoms Headache, visual
midpregnancy had been used as diagnostic criteria, even
disturbances, convulsions
when the absolute values were <140/90 mmHg. [These
Pulmonary edema
increments are no longer used to define hypertension, but it is
recommended that such women be observed more closely
because eclamptic seizures develop in some whose blood
 INDICATORS OF PREECLAMPSIA SEVERITY
pressures have stayed below 140/90 mmHg.]  The markers are also used to classify preeclampsia syndrome
 DELTA HYPERTENSION: a sudden rise in mean arterial severity. The criteria used were listed below, which are
pressure but still in a normal range; may signify preeclampsia. categorized as ‘severe’ versus ‘nonsevere’.

 CONCEPT OF ‘DELTA HYPERTENSION’ TABLE 40-2. INDICATORS OF SEVERITY OF

GESTATIONAL HYPERTENSIVE DISORDERS
 There is a substantial increase in blood pressure but remains
ABNORMALITY NONSEVERE SEVERE
still <140/90 mmHg.
Diastolic BP <110 mmHg ≥ 110 mmHg
 Some women will have an obvious preeclampsia, and some
Systolic BP <160 mmHg ≥ 160 mmHg
even develop eclamptic seizures or HEELP (Hemolysis,
Proteinuria None to positive None to positive
Elevated Liver enzyme levels, Low Platelet count)
Headache Absent Present
syndrome while still normotensive.
Visual disturbances Absent Present
Upper abdominal pain Absent Present
 GESTATIONAL HYPERTENSION
Oliguria Absent Present
 This diagnosis is made in women whose blood pressures Convulsion (eclampsia) Absent Present
reach 140/90 mmHg for the first time after midpregnancy, Serum creatinine Normal Elevated
but in whom proteinuria is not identified. Thrombocytopenia Absent Present
 Almost half of these women subsequently develop Serum transaminase Minimal Marked
preeclampsia syndrome. 10% of eclamptic seizures develop elevation
before overt proteinuria can be detected. Fetal-growth Absent Present
 Gestational hypertension is reclassified as TRANSIENT restriction
HYPERTENSION if evidence for preeclampsia does not Pulmonary edema Absent Present
develop and the blood pressure returns to normal by 12 Gestational age Late Early
weeks postpartum.
 HEADACHES and VISUAL DISTURBANCES such as
 PREECLAMPSIA SYNDROME SCOTOMATA can precede preeclampsia, which is a
convulsion not attributable to another cause.
 SEIZURES: are generalized and may appear before, during or  Gestational hypertensive disorders are more likely to
after labor. The proportion that develops seizures later, after develop in women with the following characteristics:
48 hours postpartum, approximates 10%.  Are exposed to chorionic villi for the first time
 EPIGASTRIC/ RIGHT UPPER QUADRANT PAIN: another  Are exposed to superabundance of chorionic villi, as with
symptom that frequently accompanies hepatocellular the twins or hydatidiform mole
necrosis, ischemia and edema that ostensibly stretches  Have preexisting conditions associated with endothelial
Glisson capsule. cell activation or inflammation, such as diabetes,
 This characteristic pain is frequently accompanied by obesity, cardiovascular or renal disease, immunological
elevated serum hepatic transaminase levels. disorders, or hereditary influences
 THROMBOCYTOPENIA: also signifies worsening  Are genetically predisposed to hypertension developing
preeclampsia. during pregnancy
 It represents platelet activation and aggregation as well  A fetus is not a requisite for preeclampsia to develop and
as microangiopathic hemolysis. chorionic villi need not be intrauterine since preeclampsia
 Other factors indicative of severe preeclampsia include renal can develop with an abdominal pregnancy.
or cardiac involvement, obvious fetal-growth restriction,  Regardless of precipitating etiology, the cascade of events
and early-onset disease. leading to the preeclampsia syndrome is characterized by
 The more profound these signs and symptoms, the less likely abnormalities that result in systemic vascular endothelial
it is that they can be temporized, and the more likely that damage with resultant vasospasm, transudation of plasma,
delivery will be required. and ischemic and thrombotic sequelae.
 A caveat is that differentiation between non-severe and severe
gestational hypertension or preeclampsia can be misleading  PHENOTYPIC EXPRESSION OF PREECLAMPSIA
because what might be apparently mild disease may progress SYNDROME
rapidly to severe disease.
 Two major subtypes are differentiated by whether or not
remodeling of uterine spiral arterioles by endovascular
 PREECLAMPSIA SUPERIMPOSED ON CHRONIC
trophoblasts is defective.
HYPERTENSION
 This concept has given rise to the “TWO-STAGE
 Any chronic hypertensive disorder, regardless of its cause, DISORDER” THEORY OF PREECLAMPSIA
predisposes a woman to develop superimposed preeclampsia PATHOGENESIS.
syndrome.  STAGE 1: is caused by faulty endovascular trophoblastic
 CHRONIC UNDERLYING HYPERTENSION: is diagnosed in remodeling that downstream causes the stage 2 clinical
women with documented blood pressures > 140/90 mmHg syndrome.
before pregnancy or before 20 weeks’ gestation, or both.  STAGE 2: can be modified by preexisting maternal
 Blood pressure normally drops during the second and early conditions that are also manifested by endothelial cell
third trimesters in both normotensive and chronically activation or inflammation and are listed in the third prior
hypertensive women. bullet.
 If new-onset or worsening baseline hypertension is
accompanied by new-onset proteinuria or other findings,  ETIOLOGY
then superimposed preeclampsia is diagnosed.
 The mechanisms that are currently considered important
 Compared with ‘pure’ preeclampsia, superimposed
include:
preeclampsia commonly develops earlier in pregnancy. It
1. Placental implantation with abnormal trophoblastic
tends to be more severe and more often is accompanied by
invasion of uterine vessels
fetal-growth restriction.
2. Immunological maladaptive tolerance between
maternal, paternal (placental), and fetal tissues
INCIDENCE AND RISK FACTORS 3. Maternal maladaptation to cardiovascular or
 Young and nulliparous women are particularly vulnerable to inflammatory changes of normal pregnancy
developing preeclampsia, whereas older women are at 4. Genetic factors including inherited predisposing genes
greater risk for chronic hypertension with superimposed and epigenetic influences.
preeclampsia.
 The incidence is markedly influenced by race and ethnicity- ○ ABNORMAL TROPHOBLASTIC INVASION
and thus, by genetic predisposition.  Normal implantation is characterized by extensive
 White: 5% < Hispanic: 9% < African-American: 11% remodeling of the spiral arterioles within the decidua
 Black women have greater morbidity basalis. Endovascular trophoblasts replace the vascular
 Nulliparous women: 3-10% endothelial and muscular linings to enlarge the vessel
 Multiparas: varies from 1.4- 4% diameter. The veins are invaded only superficially.
 Clinical factors: metabolic syndrome and  In some cases of preeclampsia, trophoblastic invasion
hyperhomocysteinemia may be incomplete.
 Pregnancy with a male fetus are also at slightly higher risk  The decidual vessels, but not myometrial vessels, become
 Smoking during pregnancy causes various adverse lined with endovascular trophoblasts.
pregnancy outcomes, but it carries a reduced risk for  The deeper myometrial arterioles thus do not lose their
hypertension during pregnancy. endothelial lining and musculoelastic tissue, and their
 Human immunodeficiency virus (HIV) seropositivity and mean external diameter is only that of corresponding
sleep-disordered breathing vessels in normal placentas.
 The magnitude of defective trophoblastic invasion
ETIOPATHOGENESIS correlates with the severity of the hypertensive disorder.
 It is more prevalent in women with early-onset  Cytokines such as tumor necrosis factor- α (TNF-α ) and the
preeclampsia. interleukins may contribute to the systemic oxidative stress
 Early preeclamptic changes include endothelial damage, associated with preeclampsia.
insudation of plasma constituents into vessel walls,  This is characterized by reactive oxygen species and free
proliferation of myointimal cells, and medial necrosis. radicals that lead to formation of self-propagating lipid
 ATHEROSIS: refers to lipid accumulation in myointimal peroxides.
cells and macrophages. These findings are more common  These peroxides in turn generate highly toxic radicals that
in placentas from women diagnosed with preeclampsia injure systemic vascular endothelial cells, modify nitric
before 34 weeks. oxide production by these cells, and interfere with
 The abnormally narrow lumen of spiral arterioles -> impairs prostaglandin balance.
placental blood flow -> diminished perfusion and a hypoxic  Other consequences of oxidative stress include:
environment-> release of placental debris or microparticles.  Production of the lipid-laden macrophage foam
 These changes incite a systemic inflammatory response, cells seen in placental atherosis,
which is STAGE 2 OF THE PREECLAMPSIA SYNDROME.  Activation of systemic microvascular coagulation
 Defective placentation is posited to further cause the manifested by thrombocytopenia, and
susceptible woman to develop gestational hypertension, the  Greater systemic capillary permeability reflected by
preeclampsia syndrome, preterm delivery, a edema and proteinuria.
growth-restricted fetus, and/or placental abruption.
○ GENETIC FACTORS
○ IMMUNOLOGICAL FACTORS
 Preeclampsia appears to be a multifactorial, polygenic
 Loss of the maternal immune tolerance to paternally disorder. Thus, the clinical manifestation in any given woman
derived placental and fetal antigens is another cited theory with the preeclampsia syndrome will occupy a spectrum.
for preeclampsia.  Phenotypic expression will differ among similar genotypes
 The histological changes at the maternal-placental interface depending on interactions with environmental components.
are suggestive of acute graft rejection.
 Data suggests that preeclampsia is an immune-mediated  PATHOGENESIS
disorder.
 The risk of preeclampsia is appreciably enhanced in ○ VASOSPASM
circumstances in which formation of blocking antibodies to  Systemic endothelial activation causes vasospasm that
placental antigenic sites might be impaired. Thus, the first elevates resistance to produce subsequent hypertension.
pregnancy would carry a higher risk.  At the same time, systemic endothelial cell injury promotes
 Tolerance dysregulation might also explain an elevated risk interstitial leakage, and blood constituents, including
when the paternal antigenic load is increased, that is, with platelets and fibrinogen, are deposited subendothelially.
two sets of paternal chromosomes- a ‘double dose’. Hence,  Endothelial junctional proteins are also disrupted, and the
women with molar pregnancies have a high incidence of subendothelial region of resistance arteries undergoes
early-onset preeclampsia. ultrastructural change.
 Women with a trisomy 13 fetus also have a 30- to 40-  With diminished blood flow due to maldistribution from
percent incidence of preeclampsia. These women have vasospasm and interstitial leakage, ischemia of the
elevated serum levels of antiangiogenic factors. surrounding tissues can lead to necrosis, hemorrhage, and
 Women previously exposed to paternal antigens, such as a other end-organ disturbances characteristic of the
prior pregnancy with the same partner, are ‘immunized’ syndrome. (There is markedly attenuated blood volume seen in
against preeclampsia. women with severe preeclampsia)
 In women destined to be preeclamptic, extravillous
trophoblasts early in pregnancy express reduced amounts of ○ ENDOTHELIAL CELL INJURY
immunosuppressive nonclassic human leukocyte antigen G
(HLA G).  Injury to systemic endothelial cells is now a centerpiece of
 T-helper (Th) lymphocytes during normal pregnancy are preeclampsia pathogenesis.
produced so that type 2 activity is increased in relation to  Protein factors- likely placental- are secreted into the
type 1 called as TYPE 2 BIAS. Th2 cells promote humoral maternal circulation and provoke activation and
immunity, whereas Th1 cells stimulate inflammatory dysfunction of the systemic vascular endothelium.
cytokine secretion. Th1 action is increased in the early 2nd  Intact endothelium has anticoagulant properties. Systemic
trimester. endothelial cells blunt the response of vascular smooth
muscle to agonists by releasing nitric oxide.
○ ENDOTHELIAL CELL ACTIVATION  Injured or activated endothelial cells may produce less
nitric oxide and may secrete substances that promote
 Inflammatory changes are believed to be a continuation of coagulation and greater sensitivity to vasopressors.
stage 1 alterations. In response to ischemia or other inciting  Further evidence of endothelial activation includes the
causes, placental factors are released and begin a cascade of characteristic changes in glomerular capillary endothelial
events. morphology, greater capillary permeability, and elevated
 Thus, antiangiogenic and metabolic factors and other blood concentrations of substances associated with
inflammatory leukocyte mediators are thought to provoke endothelial activation.
systemic endothelial cell injury -> ENDOTHELIAL CELL
ACTIVATION/ DYSFUNCTION ○ INCREASED PRESSOR RESPONSES
 Endothelial cell dysfunction may result from an extreme
activated state of leukocytes in the maternal circulation.  Pregnant women normally develop refractoriness to
infused vasopressors.
  Women with early preeclampsia have enhanced vascular  These high levels in the 2nd trimester are associated
reactivity to infused norepinephrine and angiotensin II. with a doubling of risk for preeclampsia.
 Increased sensitivity to angiotensin II clearly precedes 2. SOLUBLE ENDOGLIN (sEng): a second antiangiogenic
the onset of gestational hypertension. peptide, inhibits various transforming growth factor
 Women who develop preterm preeclampsia have lower beta (TGF-β) isoforms from binding to endothelial
circulating levels of angiotensin II. receptors.
 Several prostaglandins are thought to be central to  Decreased binding to endoglin diminishes
preeclampsia syndrome pathophysiology. endothelial nitric oxide-dependent vasodilation.
 The blunted pressor response seen in normal pregnancy is
 Serum levels of sEng also begin to rise months
at least partially due to diminished vascular
before clinical preeclampsia develops.
responsiveness mediated by endothelial prostaglandin
 Metformin reduces antiangiogenic secretion from
synthesis.
 For example: compared with normal pregnancy, human tissues.
endothelial prostacyclin (PGI2) production is lower in  Concentrations of the soluble forms are not higher in fetal
preeclampsia. This action appears to be mediated by circulation or amniotic fluid of preeclamptic women, and
phospholipase A2. At the same time, thromboxane A2 their levels in maternal blood dissipate after delivery.
secretion by platelets is increased, and the prostacyclin:
thromboxane A2 ratio declines. The net result favors PATHOPHYSIOLOGY
greater sensitivity to infused angiotensin II and
vasoconstriction. (These changes are apparent as early as  These are thought to be a consequence of endothelial
22 weeks’ gestation in gravidas who later develop dysfunction, vasospasm, and ischemia.
preeclampsia)
 NITRIC OXIDE: is a potent vasodilator synthesized from  CARDIOVASCULAR SYSTEM
I-arginine by endothelial cells.  Cardiovascular disturbances are common with preeclampsia
 Inhibition of nitric oxide synthesis raises mean arterial syndrome. These are related to:
pressure, lowers heart rate, and reverses the (1) GREATER CARDIAC AFTERLOAD: caused by hypertension;
pregnancy-induced refractoriness to vasopressors. (2) CARDIAC PRELOAD: which is reduced by a pathologically
 Nitric oxide is likely the compound that maintains the diminished volume expansion during pregnancy and which is
normal low-pressure vasodilated state characteristic of increased by intravenous crystalloid or oncotic solutions; and
fetoplacental perfusion. (3) ENDOTHELIAL ACTIVATION: leading to interendothelial
 It appears that the syndrome is associated with decreased extravasation of intravascular fluid into the extracellular space
endothelial nitric oxide synthase expression, thus and, into the lungs.
resulting in lower nitric oxide activity.
 ENDOTHELINS: are 21-amino-acid peptides and potent  HEMODYNAMIC CHANGES AND CARDIAC FUNCTION
vasoconstrictors. ENDOTHELIN-1 (ET-1) is the primary
isoform produced by human endothelium.  The cardiovascular aberrations vary depending on several
 Plasma endothelin-1 levels are elevated in normotensive modifiers. These factors include preeclampsia severity,
pregnant women, but women with preeclampsia have hypertension severity, presence of underlying chronic
even higher levels. disease, and the part of the clinical spectrum in which
 Placenta is not the source of increased ET-1 these are studied.
concentrations, and likely arise from systemic endothelial  These cardiovascular changes may precede hypertension.
activation. With the clinical onset of preeclampsia, cardiac output
 Treatment of preeclamptic women with magnesium declines, due to at least in part to greater peripheral
sulfate lowers ET-1 concentrations. resistance.
 When assessing cardiac function in preeclampsia,
○ ANGIOGENIC AND ANTIANGIOGENIC PROTEINS consideration is given to echocardiographic measure of
myocardial function and to clinically relevant ventricular
 Placental vasculogenesis is evident by 21 days after function.
conception.
 ANGIOGENIC IMBALANCE: it describes excessive ○ MYOCARDIAL FUNCTION
amounts of antiangiogenic factors, which are thought to
 Of women with preeclampsia, serial echocardiographic
be stimulated by worsening hypoxia at the uteroplacental
studies document diastolic dysfunction in 40-45%.
interface.
 With this dysfunction, ventricle do not properly relax and
 Trophoblast of women destined to develop preeclampsia
cannot fill properly.
overproduces at least 2 antiangiogenic peptides that  Diastolic dysfunction stems from VENTRICULAR
enter the maternal circulation: REMODELING, which is judged to be an adaptive response
1. SOLUBLE FMS-LIKE TYROSINE KINASE I (sFlt-1): is a to maintain normal contractility despite the increased
receptor for VEGF. afterload of preeclampsia.
 Elevated maternal sFlt-1 levels inactivate and  These changes are usually clinically inconsequential, but
reduce circulating free placental growth factor when combined with underlying ventricular dysfunction
(PIGF) and VEGF concentrations, leading to e.g. concentric ventricular hypertrophy from chronic
endothelial dysfunction hypertension- further diastolic dysfunction may cause
 sFlt-1 levels begin to rise in maternal serum cardiogenic pulmonary edema.
months before preeclampsia is evident.
○ VENTRICULAR FUNCTION
  Abnormally low platelets do not develop in the fetuses of
 In some preeclamptic women, cardiac troponin levels are
neonates born to preeclamptic women despite severe
slightly elevated, and amino-terminal pro-brain natriuretic
maternal thrombocytopenia.
peptide (Nt pro-BNP) levels are elevated with severe
 Thus, maternal thrombocytopenia in a hypertensive
preeclampsia.
woman is not a fetal indication for cesarean delivery.
 Both normally pregnant women and those with preeclampsia
syndrome can have normal or slightly hyperdynamic
 HEMOLYSIS
ventricular function. Thus, both have a cardiac output that is
appropriate for left-sided filling pressures.  Severe preeclampsia is frequently accompanied by
 Filling pressures are dependent on the volume of hemolysis, which manifests as elevated serum lactate
intravenous fluids. Thus, aggressive hydration results in dehydrogenase levels and reduced haptoglobin levels.
OVERTLY HYPERDYNAMIC VENTRICULAR FUNCTION.  These derangements result in part from microangiopathic
 This is accompanied by elevated pulmonary capillary hemolysis caused by endothelial disruption with platelet
wedge pressures, and pulmonary edema may develop adherence and fibrin deposition.
despite normal ventricular function. (This is because of an  Abnormally elevated serum liver transaminase levels that
alveolar endothelial-epithelial leak, and it is compounded indicated hepatocelullar necrosis. This referred as HELLP
by a decreased oncotic pressure from a low serum albumin syndrome.
concentration.)
 In sum, aggressive fluid administration to otherwise  COAGULATION CHANGES
normal women with severe preeclampsia substantially
elevates normal left-sided filling pressures and raises a  Subtle changes consistent with intravascular coagulation
physiologically normal cardiac output to hyperdynamic and less often erythrocyte destruction, commonly are found
levels. with preeclampsia and especially eclampsia.
 Some of these changes include elevated factor VIII
 BLOOD VOLUME consumption, increased levels of fibrinopeptides A and
B and of D-dimers, and reduced levels of regulatory
 HEMOCONCENTRATION: is a hallmark of eclampsia. proteins- antithrombin III and protein C and S.
 Women of average size have a blood volume of 3000 ml,  Coagulation aberrations generally are mild and are seldom
and during the last several weeks of a normal pregnancy, clinically significant.
this averages 4500ml.  Unless placental abruption is comorbid, plasma fibrinogen
 With eclampsia, much or all of the anticipated 1500ml levels do not differ remarkably from levels found in normal
excess is lost. pregnancy.
 Such hemoconcentration results from generalized  Fibrin degradation products such as D-dimers are
vasospasm that follows endothelial activation and leakage minimally elevated.
of plasma into the interstitial space.  Despite these changes, routine laboratory assessments of
 In women with preeclampsia, and depending on its coagulation, such as prothrombin time (PT), activated partial
severity, hemoconcentration is usually not as marked. thromboplastin time (aPTT), and plasma fibrinogen level, are
 Vasospasm and endothelial leakage of plasma persist for a not required in the management of pregnancy-associated
variable time after delivery as the endothelium is restored to hypertensive disorders.
normalcy.
 As this take place, vasoconstriction reverses, and as the  ENDOCRINE AND HORMONAL ALTERATIONS
blood volume reexpands, the hematocrit usually falls.
 A substantive cause of this fall in hematocrit, is usually  Plasma levels of renin, angiotensin II, angiotensin 1-7,
the blood loss incurred at delivery. aldosterone, deoxycorticosterone, and atrial natriuretic
peptide (ANP) are substantively augmented during normal
 MATERNAL THROMBOCYTOPENIA pregnancy.
 ANP: is released during atrial wall stretching from blood
 The platelet count is routinely measured in women with volume expansion, and it responds to cardiac contractility.
any form of gestational hypertension.  Levels of serum ANP rise in pregnancy, and its secretion is
 OVERT THROMBOCYTOPENIA: defined by a platelet count further enhanced in women with preeclampsia.
< 100,000/μL- indicates severe disease.  Levels of its precursors- PROATRIAL NATRIURETIC
 The lower the platelet count, the higher the rates of PEPTIDE- are also increased in preeclampsia
maternal and fetal morbidity and mortality.  VASOPRESSIN: levels are similar in nonpregnant,
 In most cases, delivery is advisable because worsening normally pregnant, and preeclamptic women even though
thrombocytopenia usually ensues.. during the metabolic clearance is elevated in the latter
 After delivery, the platelet count may continue to decline two.
for the first day or so. It then usually rises progressively to
reach a normal level within 3-5 days.  FLUID AND ELECTROLYTE ALTERATIONS
 In some instances with HELLP syndrome, the platelet
continues to fall after delivery. If these do not reach a nadir  In women with severe preeclampsia, the volume of
until 48-72 hours, then preeclampsia syndrome may be extracellular fluid, manifests as edema, is usually much
incorrectly attributed to one of the thrombotic greater than than in normal pregnant women.
microangiopathies.  The mechanism responsible for pathological fluid
 In most studies, vitro platelet aggregation is reduced retention is endothelin injury.
compared with the normal increase that is characteristic of  In addition to generalized edema and proteinuria, these
pregnancy. This is likely due to platelet ‘exhaustion’ following women have reduced plasma oncotic pressure. This
in vivo activation. reduction creates a filtration imbalance and further
 displaces intravascular fluid into the surrounding ratio values, 24-hours protein excretion should be
interstitium. quantified.
 Electrolyte concentrations do not differ appreciably in  With urine dipstick assessment: determinations depend on
women with preeclampsia compared with those of normal urine concentration and are notorious for false-positive and
pregnant women. negative results.
 Following an eclamptic convulsion: the serum pH and  Thus, assessment may show a dipstick value of 1+ to 2+
bicarbonate concentration are lowered. This is due to lactic from concentrated urine specimens from women who
acidosis and compensatory respiratory loss of carbon excrete < 300 mg/d.
dioxide.  Proteinuria may develop late, and some women may
 The intensity of acidosis relates to the amount of lactic already be delivered or have had an eclamptic convulsion
acid produced- METABOLIC ACIDOSIS- and the rate at before it appears.
which carbon dioxide is exhaled- RESPIRATORY  10-15% of women with HELLP syndrome do not have
ACIDOSIS. proteinuria at presentation
 17% of eclamptic women did not have proteinuria by the
 KIDNEY time of seizures.
 During normal pregnancy, renal blood flow and glomerular
○ ANATOMICAL CHANGES
filtration rate rise appreciably.
 Renal perfusion and glomerular filtration are reduced.  Glomeruli are enlarged by approximately 20%, they are
 Most of the decrement in glomerular filtration is from ‘bloodless’ and capillary loops variably are dilated and
higher renal afferent arteriolar resistance that may be contracted. Endothelial cells are swollen- termed as
elevated up to fivefold. GLOEMRULAR CAPILLARY ENDOTHELIOSIS.
 Morphologic changes are characterized by GLOMERULAR  Endothelial cells are often so swollen that they block or
ENDOTHELIOSIS, which blocks the barrier that allows partially block the capillary lumens.
filtration.  Homogenous subendothelial deposits of proteins and
 Diminished filtration causes serum creatinine levels to fibrin-like material are seen.
rise to values seen in nonpregnant individuals, that is, 1  Endothelial swelling may result from angiogenic protein
mg/L, and sometimes higher. Abnormal values usually ‘withdrawal’ caused by the complexing of free angiogenic
begin to normalized 10days or later after delivery. proteins with a compatible circulating antiangiogenic protein
 In most preeclamptic women, the urine sodium receptor.
concentration is elevated. Urine osmolality rises, urine:  The angiogenic proteins are crucial for podocyte health,
plasma creatinine ratio is elevated, and fractional and their inactivation leads to podocyte dysfunction and
excretion of sodium is low. endothelial swelling.
 These are all indicated that a PRERENAL MECHANISM is  Eclampsia is characterized by greater excretion of these
involved. epithelial podocytes.
 Sodium-containing crystalloid infusion raises left
ventricular filling pressure, and although oliguria temporarily ○ ACUTE KIDNEY INJURY
improves, rapid infusions may cause clinically apparent
 Although mild degrees of acute kidney injury are
pulmonary edema.
encountered, clinically apparent ACUTE TUBULAR
 Intensive intravenous fluid therapy is not indicated as
NECROSIS is almost invariably induced by comorbid
‘treatment’ for preeclamptic women with oliguria unless
hemorrhage with hypovolemia and hypotension.
urine output is diminished from hemorrhage or fluid loss
 This is usually caused by severe obstetrical bleeding-
from vomiting or fever.
especially placental abruption- coupled with inadequate
 Plasma uric acid concentration is typically elevated in
blood replacement.
preeclampsia. This is attributable to the reduction in
 Irreversible renal cortical necrosis develops rarely.
glomerular filtration rate and likely due to enhanced
tubular reabsorption.
 Preeclampsia is also associated with diminished urinary  LIVER
excretion of calcium, perhaps due to greater tubular  The characteristic hepatic lesions with eclampsia are regions
reabsorption. of periportal hemorrhage in the liver periphery.
 Hemolysis and thrombocytopenia with eclampsia, this
○ PROTEINURIA constellation of hemolysis, hepatocellular necrosis, and
thrombocytopenia was later termed HELLP SYNDROME.
 Detection of proteinuria helps to establish the diagnosis of
 Liver involvement with preeclampsia may clinically display at
preeclampsia.
least three manifestations:
 ABNORMAL PROTEIN EXCRETION: is empirically
1. Pain is considered as a sign of severe disease.
defined by a 24-hour urinary excretion exceeding 300 mg;
 It typically manifests by moderate-to-severe right upper
a urine protein: creatinine ratio ≥ 0.3; or persistent
quadrant or midepigastric pain and tenderness.
protein values of 30 mg/dl (1+ dipstick) in random urine
 Such women usually have elevated serum aspartate
samples.
transaminase (AST) or alanine transaminase (ALT)
 For a 24-hour quantification specimen, the ‘consensus’
levels.
threshold value used is ≥ 300mg/24 h. (American College of
 In some cases, the amount of hepatic tissue involved with
Obstetricians and Gynecologists, 2013)
infarction may be surprisingly extensive yet still clinically
 Using a urinary protein excretion threshold of 165 mg in a
insignificant.
24 hr sample show equivalent efficacy.
 Midrange ratios, that is, 300 mg/g or 0.3, have poor sensitivity
and specificity. Thus, many recommend that with midrange
  Infarction may be worsened by hypotension from ○ CEREBROVASCULAR PATHOPHYSIOLOGY
obstetrical hemorrhage, and it occasionally causes hepatic
 Clinical, pathological, and neuroimaging findings have led to
failure- also called SHOCK LIVER.
two general theories to explain cerebral abnormalities with
2. Elevations of serum AST and ALT levels are markers for
eclampsia.
severe preeclampsia.
1. The first theory suggests that in response to acute and
 Values seldom exceed 500 U/L but levels reaching more
severe hypertension, cerebrovascular overregulation leads to
than 2000 U/L have been reported.
vasospasm.
 In general, serum concentrations inversely follow platelet
 In this scheme, diminished cerebral blood flow is
levels, and they both usually normalize within 3 days
hypothesized to result in ischemia, cytotoxic edema, and
following delivery.
eventually tissue infarction.
3. Hemorrhagic infarction may extend to form a hepatic
2. The second theory is that sudden elevations in systemic
hematoma.
blood pressure exceed the normal cerebrovascular
 This in turn can extend to form a subcapsular hematoma
autoregulatory capacity.
that may rupture.
 Regions of forced vasodilation and vasoconstriction
 Computed tomography (CT) scanning or magnetic
develop, especially in arterial boundary zones.
resonance (MR) imaging greatly aids diagnosis,
 At the capillary level, disruption of end-capillary pressure
 Unruptured hematomas are probably more common than
causes increased hydrostatic pressure, hyperperfusion,
clinically suspected and are more likely to be found with
and extravasation of plasma and red cells through
HELLP syndrome.
endothelial tight-junction openings. This leads to
 Although once considered a surgical condition, current
VASOGENIC EDEMA.
management of a hepatic hematoma usually consists of
 The most likely mechanism is a combination of the two. Thus,
observation unless bleeding is ongoing. In some cases,
a preeclampsia-associated interendothelial cell leak develops
prompt surgical intervention or angiographic
at blood pressure (hydraulic) levels much lower than those
embolization may be lifesaving.
that usually cause vasogenic edema and is coupled with a loss
 ACUTE FATTY LIVER OF PREGNANCY: is sometimes
of upper-limit autoregulation.
confused with preeclampsia.
 With imaging studies, these manifest as the POSTERIOR
 It also has an onset in late pregnancy, and often there is
REVERSIBLE ENCEPHALOPATHY SYNDROME.
accompanying hypertension, elevated serum
 The lesions of this syndrome principally involve the
transaminase and creatinine levels, and
posterior brain- the occipital and parietal cortices.
thrombocytopenia.
 The hallmark of acute fatty liver is significant liver
dysfunction. ○ CEREBRAL BLOOD FLOW
 AUTOREGULATION: is the mechanism by which cerebral
○ HELLP SYNDROME blood flow remains relatively constant despite alterations in
cerebral perfusion pressure.
 Complications include eclampsia (6%), placental abruption
 CEREBRAL PERFUSION PRESSURE: is the difference
(10%), acute kidney injury (5%), and pulmonary edema
between mean arterial pressure and intracranial pressure.
(10%).
 In nonpregnant women, this autoregulation protects the
 Stroke, hepatic hematoma, coagulopathy, acute
brain from hyperperfusion when mean arterial pressures
respiratory distress syndrome, and sepsis were other
rise to as high as 160 mmHg.
serious complications.
 Thus, to explain eclamptic seizures, it was theorized that
 Women with preeclampsia and HELLP syndrome typically
autoregulation must be altered by pregnancy.
have worse outcomes than preeclamptic women without
 It was showed that cerebral blood flow during the first two
HELLP syndrome.
trimesters of normal pregnancy is similar to nonpregnant
values. But, during the last trimester, flow significantly
 BRAIN
drops by 20%.
 Headaches and visual symptoms are common with severe  These findings suggest that eclampsia occurs when cerebral
preeclampsia, and associated convulsions define hyperperfusion forces capillary fluid interstitially because
eclampsia. of endothelial damage.
 This leak leads to perivascular edema characteristic of the
○ NEUROANATOMICAL LESIONS preeclampsia syndrome.
 Brain pathology accounted for only about a third of fatal
○ NEUROLOGICAL MANIFESTATIONS
cases. Most deaths were from pulmonary edema, and brain
lesions were coincidental.  Several neurological manifestations typify the preeclampsia
 Other principal lesions found at autopsy of eclamptic women syndrome.
were cortical and subcortical petechial hemorrhages. 1. Headache and scotomata: are thought to arise from
 The classic microscopic vascular lesions consist of fibrinoid cerebrovascular hyperperfusion that has a predilection for the
necrosis of the arterial wall and perivascular microinfarcts occipital lobes.
and hemorrhages.  Up to 75% of women have headaches, and 20-30% have
 Other frequently described major lesions include subcortical visual changes preceding eclamptic convulsions.
edema, multiple nonhemorrhagic areas of ‘softening’  The headaches may be mild to severe and intermittent to
throughout the brain, and hemorrhagic areas in the white constant.
matter.  They are unique in that they do not usually respond to
 There also may be hemorrhage in the basal ganglia or pons, traditional analgesia, but they frequently improve after
sometimes with rupture into the ventricles. magnesium sulfate infusion.
2. Convulsions are diagnostic for eclampsia.
 These are caused by excessive release of excitatory
neurotransmitters- especially glutamate; massive
depolarization of network neurons; and bursts of action
potentials.
 Extended seizures can cause significant brain injury and
later brain dysfunction.
3. Blindness: is rare with preeclampsia alone, but it complicates
eclamptic convulsions in up to 15% of women.
 Blindness may develop up to a week or more following
delivery.
4. Generalized cerebral edema: may develop and is usually
manifest by mental status changes that vary from confusion to
coma.
 This situation is particularly dangerous because fatal
transtentorial herniation can result.
5. Last, women with eclampsia have been shown to have some
cognitive decline.