Hypertensive Disorders of Pregnancy
Hypertensive disorders are the most common medical
complications of pregnancy, affecting 5% to 10% of all
pregnancies. These disorders are responsible for approximately
16% of maternal mortality in developed countries. Classification of
hypertensive disorders in pregnancy includes chronic hypertension
and the group of hypertensive disorders unique to pregnancy
including gestational hypertension and preeclampsia.
Approximately 30% of hypertensive disorders in pregnancy are
due to chronic hypertension, and 70% are due to gestational
hypertension. The spectrum of disease ranges from mildly elevated
blood pressures with minimal clinical significance to severe
hypertension and multi organ dysfunction. The incidence of
disease is dependent on many different demographic parameters,
including
1- Maternal age,
2-race,
3-and associated underlying medical conditions.
Definitions and Classifications
Hypertension is defined as a systolic blood pressure (SBP) of 140
mm Hg or greater or a diastolic blood pressure (DBP) of 90 mm
Hg or greater. These measurements must be present on at least two
occasions at least 6 hours apart but no more than 1 week apart. In
order to reduce inaccurate readings, an appropriate size of cuff
should be used (length 1.5 times upper arm circumference).
Pressure should be taken with the patient in an upright position,
after a 10-minute or longer rest period. For patients in the hospital,
the blood pressure can be taken with either the patient sitting up or
in the left lateral recumbent position with the patient's arm at the
level of the heart. The patient should not use tobacco or caffeine
for 30 minutes preceding the measurement. Abnormal proteinuria
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in pregnancy is defined as the excretion of 300 mg or more of
protein in 24 hours. The most accurate measurement of proteinuria
is obtained with a 24-hour urine collection. However, in certain
instances, semi mquantitative dipstick measurement may be the
only mode available to assess urinary protein. A value of 1+ or
greater correlates with 30 mg/dL. Proteinuria by dipstick is defined
as 1+ or more on at least two occasions at least 6 hours apart but
no more than 1 week apart. The accuracy of semi quantitative
dipstick measurements on spot urine samples as compared with 24hour urine collections is highly variable. Therefore, should time
allow, a 12-hour or 24-hour urine collection should be performed
as part of the diagnostic criteria to define proteinuria. When
obtaining urine protein measurements, care should be taken to use
a clean sample, because blood, vaginal secretions, and bacteria can
increase the amount of protein in urine.
Edema is a common finding in the gravid patient, occurring in
approximately 50% of women. Lower extremity edema is the most
typical form. Pathologic edema is seen in nondependent regions
such as the face, hands, or lungs. Excessive, rapid weight gain of 5
pounds or more per week is another sign of fluid retention.
Classification of Hypertension in Pregnancy with Definitions
Disorder
Definition
Hypertension developing after 20 weeks
Gestational
gestation or during the first 24 hours postpartum
hypertension
without proteinuria or other signs of
preeclampsia
Hypertension that resolves by 12 weeks
Transient
postpartum
hypertension
Hypertension that does not resolve by 12 weeks
Chronic
postpartum
hypertension
Preeclampsia or Hypertension typically developing after 20
weeks gestation with proteinuria; eclampsia is
eclampsia
the occurrence of seizure activity without other
identifiable causes
2
Chronic
hypertension
Preeclampsia
superimposed
Hypertension diagnosed prior to pregnancy,
prior to 20 weeks gestation, or after 12 weeks
postpartum
The development of preeclampsia or eclampsia
in a woman with preexisting or chronic
hypertension
Gestational Hypertension
Gestational hypertension is the most frequent cause of
hypertension during pregnancy. The rate ranges between 6% and
17% in healthy nulliparous women and between 2% and 4% in
multiparous women. It is considered severe if there is sustained
SBP to at least 160 mm Hg and/or DBP to at least 110 mm Hg for
at least 6 hours without proteinuria.
Preeclampsia and Eclampsia
The rate of preeclampsia ranges between 2% and 7% in healthy
nulliparous women. The rate is substantially higher in women with
twin gestation (14%) and in those with previous preeclampsia
(18%). The symptoms of preeclampsia are headaches, visual
changes, and epigastric or right upper quadrant pain plus nausea or
vomiting. In the absence of proteinuria, preeclampsia should be
considered when gestational hypertension is associated with
persistent cerebral symptoms, epigastric or right upper quadrant
pain with nausea or vomiting, fetal growth restriction, or
thrombocytopenia and abnormal liver enzymes.
Preeclampsia may be subdivided further into mild and severe
forms. The distinction between the two is made on the basis of the
degree of hypertension and proteinuria as well as the involvement
of other organ systems. Close surveillance of patients with either
mild preeclampsia or gestational hypertension is warranted,
because they may progress to fulminant disease. A particularly
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severe form of preeclampsia is the HELLP syndrome, which is an
acronym for hemolysis, elevated liver enzymes, and low platelet
count. This syndrome is manifest by laboratory findings consistent
with hemolysis, elevated levels of liver function, and
thrombocytopenia. The diagnosis may be deceptive, because
hypertension and proteinuria might be absent in 10% to 15% of
women who develop HELLP and in 20% to 25% of those who
develop eclampsia. A patient diagnosed with HELLP syndrome is
automatically classified as having severe preeclampsia. Another
severe form of preeclampsia is eclampsia, which is the occurrence
of seizures not attributable to other causes.
Criteria for the Diagnosis of Mild Preeclampsia
SBP >140 mm Hg and/or DBP >90 mm Hg on two occasions at
least 6 hours apart, typically occurring after 20 weeks gestation (no
more than 1 week apart)
Proteinuria of 300 mg in a 24-hour urine collection or >1+ on two
random sample urine dipsticks at least 6 hours apart (no more than
1 week apart)
SBP, systolic blood pressure; DBP, diastolic blood pressure.
Criteria for the Diagnosis of Severe Preeclampsia
SBP >160 mm Hg and/or DBP >110 mm Hg on two occasions at
least 6 hours apart
Proteinuria of 5 g or higher in a 24-hour urine specimen or 3+ or
greater on two random urine samples collected at least 4 hours
apart
Oliguria <500 cc in 24 hours
Thrombocytopenia—platelet count <100,000/mm3
Elevated liver function test results with persistent epigastric or
right upper quadrant pain
Pulmonary edema
Persistent, severe cerebral or visual disturbances
SBP, systolic blood pressure; DBP, diastolic blood pressure.
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Chronic Hypertension
Hypertension that complicates pregnancy is considered chronic if a
patient is diagnosed with hypertension before pregnancy, if
hypertension is present prior to 20 weeks gestation, or if it persists
longer than 12 weeks after delivery.
Chronic Hypertension with Superimposed Preeclampsia
Women with chronic hypertension are at risk of developing
superimposed preeclampsia, with the reported rate of
superimposed preeclampsia ranging from 10% to 25%.
Superimposed preeclampsia is defined as an exacerbation of
hypertension with new onset of proteinuria or symptoms of
headache or epigastric pain or laboratory abnormalities such as
elevated liver enzymes. Exacerbation of hypertension is confirmed
if there is an increase in blood pressure to the severe range (SBP of
160 mm Hg or more; DBP of 110 mm Hg or more) in a woman
whose hypertension has been well controlled.
Preeclampsia
Preeclampsia is a multisystem disorder of unknown cause that is
unique to human pregnancy. The incidence is reported to be
between 2% and 7%, depending on the population. Preeclampsia
occurs more frequently in primigravidas. The reported rate ranges
from 6% to 7% in primigravidas and from 3% to 4% in
multiparous patients. Generally, preeclampsia is regarded as a
disease of first pregnancy. Advanced maternal age (>35 years) is
another risk factor, especially if conception was secondary to
assisted reproductive technology. Obesity is another important
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factor. An overall increased rate of thrombophilia has been seen in
women with preeclampsia compared with controls.
Risk Factors for Preeclampsia
Nulliparity
Chronic or vascular disease (pregestational diabetes, renal disease,
chronic hypertension, rheumatic disease, connective tissue disease)
Molar pregnancy
Fetal hydrops
Multifetal gestation
Obesity and insulin resistance
Prior pregnancy complicated by preeclampsia
Antiphospholipid antibody syndrome and thrombophilia
Family history of preeclampsia or eclampsia
Fetal aneuploidy
Maternal infections
Maternal susceptibility genes
Extremes of maternal age
Partner-related factors (limited sperm exposure, donor
insemination [oocyte and embryo donation])
Etiology
The etiologic agent responsible for the development of
preeclampsia remains unknown. The syndrome is characterized by
vasospasm; hemoconcentration; and ischemic changes in the
placenta, kidney, liver, and brain. These abnormalities usually are
seen in women with severe preeclampsia. Theories as to the
causative mechanisms include placental origin, immunologic
origin, and genetic predisposition, among others.
Etiologic Theories in Preeclampsia
Abnormal or increased immune response
Genetic predisposition
Abnormal coagulation or thrombophilias
Abnormal angiogenesis
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Endothelial cell injury
Alterations in nitric oxide levels
Increased oxygen free radicals
Abnormal cytotrophoblast invasion
Abnormal calcium metabolism
Dietary deficiencies
Pathophysiology
Cardiovascular
The hypertensive changes seen in preeclampsia are attributed to
intense vasoconstriction with segmental spasm that occurs
particularly in arterioles and is thought to be due to increased
vascular reactivity. The underlying mechanism responsible for the
increased vascular reactivity is presumed to be alterations in the
normal interactions of vasodilatory (prostacyclin, nitric oxide) and
vasoconstrictive (thromboxane A2, endothelin) substances. These
changes lead to higher arterial blood pressures (afterload). Another
vascular hallmark of preeclampsia is hemoconcentration. Patients
with preeclampsia have lower intravascular volumes and less
tolerance for the blood loss associated with delivery. It is thought
that endothelial damage promotes leakage of intravascular fluid
and protein into the interstitial space, leading to lower intravascular
volume. The heart in a healthy woman with preeclampsia is normal
in function and contractility.
Hematologic
Several abnormalities of the coagulation system can occur. The
most common hematologic abnormality in preeclampsia is
thrombocytopenia (platelet count <100,000/mm3). The suggested
pathophysiology likely is vascular endothelial damage or
activation and higher levels of thromboxane A2. Another possible
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hematologic abnormality is microangiopathic hemolysis, as seen in
HELLP syndrome, and can be diagnosed by schistocytes seen on
peripheral smear and increased lactate dehydrogenase (LDH)
levels. Interpretation of the baseline hematocrit in a preeclamptic
patient may be difficult. A low hematocrit may signify hemolysis,
and a falsely high hematocrit may be due to hemoconcentration.
Renal
Vasospasm in preeclampsia leads to decreased renal perfusion and
subsequent decreased glomerular filtration rate (GFR). In normal
pregnancy, the GFR is increased up to 50% above prepregancy
levels. Because of this, serum creatinine levels in preeclamptic
patients rarely rise above normal pregnancy levels (0.8 mg/dL).
Close monitoring of urine output is necessary in patients with
preeclampsia, because oliguria (defined as <500 cc in 24 hours)
may occur due to renal insufficiency. Rarely, profound renal
insufficiency may lead to acute tubular necrosis. The
pathognomonic renal lesion in preeclampsia is called glomerular
capillary endotheliosis, which is swelling of the glomerular
capillary endothelial and mesangial cells.
Hepatic
Hepatic damage associated with preeclampsia can range from
mildly elevated liver enzyme levels to subcapsular liver
hematomas and hepatic rupture. The latter usually are associated
with HELLP syndrome. Approximately 20% of maternal mortality
in preeclampsia is related to hepatic complications. The pathologic
liver lesions seen on autopsy are periportal hemorrhages,
hepatocellular necrosis, ischemic lesions, intracellular fatty
changes, and fibrin deposition.
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Central Nervous System
Eclamptic convulsions are perhaps the most disturbing central
nervous system (CNS) manifestation of preeclampsia and remain a
major cause of maternal mortality in the Third World. The exact
etiology of eclampsia is unknown but is thought to be attributed to
coagulopathy, fibrin deposition, and vasospasm. The most
common finding in the brain is edema, which likely is due to
vascular autoregulation dysfunction. Radiologic studies may show
evidence of cerebral edema and hemorrhagic lesions, particularly
in the posterior hemispheres, which may explain the visual
disturbances seen in preeclampsia. Other CNS abnormalities
include headaches and visual disturbances such as scotomata;
blurred vision; and rarely, temporary blindness.
Fetus and Placenta
The hallmark placental lesion in preeclampsia is acute atherosis of
decidual arteries. This is due in part to the abnormal adaptation of
the spiral artery–cytotrophoblast interface and results in poor
perfusion. This may lead to poor placental perfusion, resulting in
oligohydramnios; intrauterine growth restriction; placental
abruption; fetal distress; and ultimately, fetal demise.
Prediction
No good screening test exists for the prediction of preeclampsia.
Several methods have been proposed but have not been found to be
cost-effective or reliable (Table 16.6). Given that nulliparity has a
5% to 7% risk of preeclampsia
P.261
and multiparity carries only a 3% risk, an accurate and thorough
maternal history with identification of risk factors is the most costeffective screening method available. Doppler ultrasonography is a
useful method to assess the velocity of uterine blood flow in the
second trimester. Abnormal velocity waveform is characterized by
a high resistance index or an early diastolic notch (unilateral or
bilateral). Data still do not support this test for routine screening.
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Recently, investigators have begun to examine soluble FMS-like
tyrosine kinase-1 receptors (sFlt-1) and placental growth factor as
early markers for preeclampsia. Future studies using proteomic and
other markers such as soluble endoglin and FMS-like tyrosine
kinase receptors (sFlt) are still ongoing.
TABLE 16.6 Proposed Methods of Prediction of Preeclampsia
Maternal serum uric acid levels
Uterine artery Doppler determinations
Elevated second-trimester MSAFP, β-hCG levels, inhibin A
Elevated sFlt-1 and endoglin
Reduced placental growth factors
Plasma fibronectin values
Midpregnancy blood pressure measurements
Urinary calcium excretion
Urinary kallikrein concentration
Platelet activation
Excessive weight gain
Calcium-to-creatinine ratio
MSAFP, maternal serum α-fetoprotein; β-hCG, β-human
chorionic gonadotropin.
TABLE 16.7 Methods to Prevent Preeclampsia
Method
Pregnancy
Recommendation
Outcome
Diet and exercise No reduction in
Insufficient evidence to
(I); protein or salt preeclampsia
recommenda
restriction (II)
Magnesium or zinc No reduction in
Insufficient evidence to
supplementation (I) preeclampsia
recommenda
Fish oil
No effect in low- or Insufficient evidence to
supplementation and high-risk
recommenda
other sources of
populations
fatty acids (I)
Calcium
Reduced
Recommended for
supplementation (I) preeclampsia in
women at high risk of
those at high risk
gestational hypertension
10
and with low
and in communities with
baseline dietary
low dietary calcium
calcium intake; no intake
effect on perinatal
outcome
Low-dose aspirin (I) 19% reduction in
Consider in high-risk
risk of preeclampsia; pregnancies
16% reduction in
fetal and neonatal
deaths
Heparin or lowReduced
Insufficient evidence to
molecular-weight preeclampsia in one recommenda
heparin (III-3)
trial
Antioxidant
No reduction in
No evidence to
vitamins (C, E) (I) large trials
recommend
Antihypertensive Risk of women
No evidence to
medications in
developing severe recommend for
women with chronic hypertension
prevention
hypertension (I)
reduced by half; no
reduction in the risk
of preeclampsia
a
Insufficient evidence refers to small trials or inconclusive results.
Levels of evidence (I–IV) as outlined by the U.S. Preventive
Task Force.
Sibai BM. Preeclampsia. Lancet 2005;365(9461):785–799.
Prevention
Preventive interventions for preeclampsia could impact maternal
and perinatal morbidity and mortality worldwide. As a result,
during the past decade, several randomized trials reported several
methods to reduce the rate and/or severity of preeclampsia. Several
trials assessed protein or low-salt diets, diuretics, bed rest, zinc,
magnesium, fish oil, or vitamin C and E supplementation and
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heparin to prevent preeclampsia in women, but results showed
minimal to no effect. Recently, the results of two large randomized
clinic trials using vitamin C and E in both healthy women and
women at high risk showed no reduction in the risk of
preeclampsia, intrauterine growth restriction, or the risk of death or
other serious outcomes in their infants. Furthermore, the World
Health Organization (WHO) conducted a randomized trial of
calcium supplementation among low-calcium-intake pregnant
women. The study showed that 1.5 g per day of calcium does not
prevent preeclampsia but did reduce its severity, maternal
morbidity, and neonatal mortality. On the other hand, a new
evidence-based review of the available scientific evidence in
regard to calcium intake and hypertensive disorder in pregnancies
did not support a benefit.
Maternal and Perinatal Outcome
Maternal and neonatal outcome in patients with preeclampsia
relates largely to one or more of the following factors: the
gestational age at delivery, severity of disease, quality of
management, and presence of preexisting disease. Perinatal
mortalities are increased in those who develop the disease at <34
weeks gestation. Risk to the mother can be significant and includes
the possible development of disseminated intravascular
coagulation (DIC), intracranial hemorrhage, renal failure, retinal
detachment, pulmonary edema, liver rupture, abruptio placentae,
and death (Table 16.8). Therefore, experienced clinicians should
be caring for women with preeclampsia.
Mild Preeclampsia
Diagnosis of Mild Preeclampsia and Gestational Hypertension
The diagnosis of mild preeclampsia requires the presence of
hypertension and proteinuria in pregnancy. Once the diagnosis is
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made, treatment is delivery. The decision for active management
versus expectant management depends on several factors: severity
of disease, gestational age, fetal and maternal status, presence of
labor, and the wishes of the mother. Because the spectrum of
disease in preeclampsia is variable, it is important to monitor
patients for the development of severe preeclampsia. Patients with
mild preeclampsia are at risk of developing eclampsia, potentially
suddenly, without warning, and with minimal blood pressure
elevations. Another risk is abruptio placentae. However, both of
these risks are less than 1%.
Maternal and Fetal Complications in Severe Preeclampsia
Maternal
Abruptio placentae (1%–4%)
Disseminated coagulopathy/HELLP syndrome (10%–20%)
Pulmonary edema/aspiration (2%–5%)
Acute renal failure (1%–5%)
Eclampsia (<1%)
Liver failure or hemorrhage (<1%)
Stroke (rare)
Death (rare)
Long-term cardiovascular morbidity
Fetal
Preterm delivery (15%–67%)
Fetal growth restriction (10%–25%)
Hypoxia–neurologic injury (<1%)
Perinatal death (1%–2%)
Long-term cardiovascular morbidity associated with low birth
weight (fetal origin of adult disease)
HELLP, hemolysis, elevated liver enzymes, low platelet count.
Sibai BM. Preeclampsia. Lancet 2005;365(9461):785–799.
Management of Mild Preeclampsia
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Ideally, a patient who has preeclampsia should be hospitalized at
the time of diagnosis. Management of the patient with mild
preeclampsia should include baseline laboratory evaluation,
including a 24-hour urine collection for protein, hematocrit,
platelet count, serum creatinine value, and aspartate
aminotransferase (AST) level. At the time of diagnosis,
ultrasonography should be performed to evaluate amniotic fluid
volume and estimated fetal weight and to confirm gestational age.
The only definitive cure for preeclampsia is delivery. The main
objective of management of preeclampsia must always be the
safety of the mother and a mature newborn who will not require
intensive and prolonged neonatal care. In patients diagnosed with
mild preeclampsia at term (>37 weeks), the general consensus is
delivery especially since perinatal outcome is similar to
normotensive pregnancy. For the patient who is preterm (<37
weeks), controversy arises regarding management with respect to
level of activity, diet, antihypertensive medications, and delivery.
Usually, these patients do not require immediate delivery, and
expectant management is warranted. Hence, the clinical decision
making in patients with mild preeclampsia is twofold. If expectant
management is chosen, the second question then becomes where to
manage the patient—in the hospital or at home?
Criteria for Home Management of Mild Preeclampsia
Ability to comply with recommendations
DBP <100 mm Hg
SBP <160 mm Hg
Normal laboratory tests and no maternal symptoms
Reassuring fetal status with appropriate growth
Urine protein of 1,000 mg or less in 24 hours
DBP, diastolic blood pressure; SBP, systolic blood pressure.
In the past, once diagnosed with mild preeclampsia, a woman was
either delivered immediately or managed in the hospital for the
remainder of the pregnancy.
Signs and Symptoms of Preeclampsia That Warrant Prompt
Evaluation
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Nausea and vomiting
Persistent severe headache
Right upper quadrant or epigastric pain
Scotoma
Blurred vision
Decreased fetal movement
Rupture of membranes
Vaginal bleeding
Regular contractions
Maternal and Fetal Evaluation in Mild Preeclampsia
Maternal
Daily weight
Urine dipstick daily; 24-hour protein once weekly
Monitoring for severe preeclampsia symptoms
Prenatal visits twice per week
Lab tests (liver function tests, hematocrit, platelet count once or
twice per week)
Fetal
Daily fetal movement
Nonstress test twice per week or biophysical profile once per week
Ultrasound for growth every 3 to 4 weeks
Optimal timing of delivery is dependent on maternal and fetal
status. In the preterm pregnancy, the sole benefit of expectant
management is for the fetus. Once a pregnancy reaches term, the
plan should be for delivery. Induction of labor is indicated in those
patients with a favorable cervix. At 37 weeks or beyond, if the
cervix is unfavorable, there are two options: either cervical
ripening and delivery or continued expectant management with
maternal and fetal evaluation. The preferred mode of delivery
remains vaginal. A cesarean section should be performed for
obstetric indications only.
In the past, while in labor, patients with mild preeclampsia
received intravenous magnesium sulfate (MgSO4) for seizure
prophylaxis. A regimen for MgSO4 administration is presented
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later in this chapter. The exact point in labor at which to start
MgSO4 remains unknown. There is no support in the literature for
the need or the optimal timing to begin the MgSO4 infusion, and
this should be left to the discretion of the physician. There are only
two double-blind, placebo-controlled trials evaluating the use of
MgSO4 in patients with mild preeclampsia. In both trials, patients
with well-defined mild preeclampsia were randomized during
labor or postpartum, and there was no difference in the percentage
of women who progressed to severe preeclampsia (12.5% vs.
13.8%; relative risk [RR] 0.90; 95% confidence interval [CI] 0.52
to 1.54). There were no instances of eclampsia among 181 patients
assigned to placebo. Thus, the authors recommend to individualize
each case for the use of MgSO4.
Pain management in labor should be individualized as well.
Intravenous narcotics and regional anesthesia are both appropriate
options. Close monitoring of blood pressure intrapartum is
necessary. Antihypertensive medications may be needed in order
to keep blood pressure values below 160 mm Hg systolic and
below 110 mm Hg diastolic. The most commonly used intravenous
medications for this purpose are labetalol and hydralazine. The
recommended dosages of medications for the immediate treatment
of hypertension are listed in Table 16.12. Care should be taken not
to drop the blood pressure too rapidly, because a marked decrease
in mean arterial pressure may lead to reduced renal perfusion and
reduced placental perfusion. Preeclamptic women who receive
MgSO4 also are at risk for postpartum hemorrhage due to uterine
atony.
Dr. Naser Malas
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