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BURDEN OF DISEASE Women with preeclampsia are at an increased risk for life-
threatening events, including placental abruption, acute renal failure, cerebral
hemorrhage, hepatic failure or rupture, pulmonary edema, disseminated intravascular
coagulation, and progression to eclampsia. Worldwide, 10 to 15 percent of direct
maternal deaths (ie, resulting from obstetric complications of pregnancy) are
associated withpreeclampsia/eclampsia [ 8 ]. In the United
States, preeclampsia/eclampsia is one of four leading causes of maternal death, along
with hemorrhage, cardiovascular conditions, and thromboembolism [ 9-11 ]. There is
approximately one maternal death due to preeclampsia-eclampsia per 100,000 live
births, with a case-fatality rate of 6.4 deaths per 10,000 cases [ 12,13 ]. In the
Netherlands between 1993 and 2005, preeclampsia was the most common cause of
maternal death, with 3.5 maternal deaths per 100,000 live births [ 14 ].
(See "Overview of maternal mortality" .)
Morbidity and mortality are also increased for the fetus/neonate because of the greater
risk of restricted fetal growth and preterm birth in affected pregnancies.
RISK FACTORS Risk factors for preeclampsia are listed in the table ( table 4 ). The
magnitude of risk depends upon the specific factor and is described below for selected
risk factors evaluated in a systematic review of controlled studies [ 15 ].
Body mass index 26.1 (RR 2.47, 95% CI 1.66-3.67) [ 15 ]. (See "The impact
of obesity on fertility and pregnancy", section on 'Pregnancy associated
hypertension' .)
Twin pregnancies (RR 2.93, 95% 2.04-4.21) [ 15 ]. The risk increases with
increasing number of fetuses in multiple gestations: triplet pregnancy triples
the risk of preeclampsia compared with twin pregnancy.
CLINICAL MANIFESTATIONS
Nausea, vomiting
Oliguria
Oligohydramnios
Laboratory abnormalities
Hemoconcentration
Thrombocytopenia (<100,000/microL)
Course Most women have only mild hypertension and mild proteinuria that
gradually worsen until delivery. In about 25 percent of women, especially those with
early onset preeclampsia, hypertension and/or proteinuria reach a severe
level and/or signs and symptoms of end-organ damage become apparent over a period
of days to weeks ( table 2 ) [ 37 ]. Two percent of these women develop eclampsia.
Severe preeclampsia can be associated with serious maternal and/or fetal sequelae
(eg, abruptio placentae; liver hematoma or rupture; disseminated intravascular
coagulation; stroke; need for mechanical ventilation, invasive hemodynamic
monitoring, transfusion, or dialysis) [ 38,39 ]. It is important to note that severe
sequelae can occur in women with mild hypertension and mild proteinuria who have
clinical evidence of significant end-organ dysfunction. Chest pain, dyspnea, low oxygen
saturation, low platelet count, and elevated creatinine and aspartate transaminase
concentrations appear to be particularly predictive of adverse outcome [ 40 ].
Delivery of the placenta always results in complete resolution of signs and symptoms
of the disease. Typically, mobilization of third-space fluid and diuresis begin within 48
hours of delivery. Hypertension may worsen during the first, and occasionally the
second, postpartum week, but normalizes in most women within four weeks
postpartum [ 41 ]. Rarely, hypertension persists beyond three months. Proteinuria
usually begins to improve within a few days, however, in women with several grams of
protein excretion, complete resolution may take weeks to months; a prolonged time to
complete resolution is more likely with severe disease [ 42 ]. Delayed postpartum
onset or exacerbation of disease is atypical (see 'Delayed postpartum onset or
exacerbation of disease' above).
Cardiopulmonary
Hypertension Hypertension is generally the earliest clinical finding of preeclampsia
and is the most common clinical clue to the presence of the disease. The blood
pressure usually rises gradually, reaching the hypertensive range (140/90 mmHg)
sometime in the third trimester, often after the 37th week of gestation [ 30 ]. However,
in some women, hypertension develops rapidly or before 34 weeks of gestation or
postpartum. A systolic blood pressure of 160 mm Hg or diastolic blood pressure of
110 mm Hg on two occasions at least six hours apart upstages preeclampsia from
mild to severe [ 4 ].
Cardiac function Preeclampsia does not affect the myocardium directly, but the
heart responds to physiological changes induced by preeclampsia. Left ventricular
ejection fraction usually remains within normal limits [ 43 ], but reductions in
longitudinal, circumferential, and radial systolic strain have been observed [ 44 ]. The
decrement in left ventricular performance in women with preeclampsia has been
attributed to a physiologic response to increased afterload [ 43-45 ], but other factors
may play a role since systolic strain was depressed in preeclamptic patients compared
to pregnant women with nonproteinuric hypertension with similar resting blood
pressure [ 44 ]. The high afterload in preeclampsia is associated with elevated cardiac
filling pressures, reflected by four-fold higher concentrations of natriuretic peptides in
women with preeclampsia compared to pregnant women who are normotensive or
have chronic hypertension [ 46 ].
Urinary protein excretion may be a late finding [ 58,59 ], but generally increases as
preeclampsia progresses. It is due, in part, to impaired integrity of the glomerular
barrier and altered tubular handling of filtered proteins (hypofiltration) leading to
increased protein excretion [ 60 ]. Both size and charge selectivity of the glomerular
barrier are affected [ 61 ]. Using special studies, podocyturia (urinary excretion of
podocytes) has been observed in patients with preeclampsia [ 62 ]. Urinary shedding
of podocytes may indicate podocyte loss from the glomerulus, which may lead to a
disruption of the glomerular filtration barrier and consequent proteinuria. Deficient
vascular endothelial growth factor (VEGF) signaling appears to account, at least in
part, for these effects. (See "Pathogenesis of preeclampsia", section on 'Pathogenesis
of systemic endothelial dysfunction' .)
Hyperuricemia and hypocalciuria are also observed; the mechanisms for these changes
are not clear [ 60,63,64 ]. The rise in serum uric acid concentration is thought to
reflect increased proximal sodium resorption and, secondarily, urate reabsorption
induced by renal ischemia. Other possible mechanisms for hyperuricemia in
preeclampsia include underlying metabolic syndrome, tissue damage, oxidative stress,
and inflammation [ 65 ].
Although hyperuricemia is associated with preeclampsia, serum uric acid level is a poor
predictor of development of the disease or maternal and fetal complications in women
with preeclampsia [ 66,67 ]. However, an elevated uric acid level (>6.0 mg/dL) at the
time of diagnosis appears to identify women at risk of delivery within seven days,
whereas a low uric acid level (4.0 mg/dL) is associated with a prolonged latency
period [ 68 ].
Loss of fenestrations
The prothrombin time, partial thromboplastin time, and fibrinogen concentration are
not affected unless there are additional complications, such as abruptio placentae or
severe liver dysfunction [ 73 ].
The white blood cell count may be slightly higher due to neutrophilia [ 74 ].
Hepatic Periportal and sinusoidal fibrin deposition and microvesicular fat deposition
are histologic findings observed in the livers of preeclamptic women [ 75,76 ]. Reduced
hepatic blood flow can lead to ischemia and periportal hemorrhage. The clinical
manifestations of hepatic dysfunction include right upper quadrant or epigastric pain,
elevated transaminase levels, coagulopathy, and, in the most severe cases,
subcapsular hemorrhage or hepatic rupture. These hepatic changes upstage the
preeclampsia from mild to severe. Nausea and vomiting may occur.
Epigastric pain is one of the cardinal symptoms of severe preeclampsia. A review of
this nonspecific symptom revealed that it is typically experienced as a severe constant
pain that begins at night, usually maximal in the low retrosternum or epigastrium, but
may radiate to the right hypochondrium or back [77 ]. The pain is thought to be due to
stretching of Glissons capsule due to hepatic swelling or bleeding. It may be the only
symptom on presentation, thus a high index of suspicion is important to make the
diagnosis of preeclampsia rather than gastroesophageal reflux, which is common in
pregnant women, especially at night. The liver may be tender to palpation.
Rarely, transient diabetes insipidus has been reported in preeclampsia with hepatic
dysfunction. (See "Renal and urinary tract physiology in normal pregnancy", section on
'DI associated with hepatic dysfunction' .)
Fetus and placenta The fetal consequences of chronic placental hypoperfusion are
fetal growth restriction and oligohydramnios. Fetal growth restriction upstages
preeclampsia from mild to severe.
Severe and early onset preeclampsia result in the greatest decrements in birth weight
compared to normotensive pregnancies, 12 and 23 percent, respectively [ 93 ]. By
comparison, late onset preeclampsia can be associated with higher than average birth
weight, possibly related to greater placental perfusion due to elevated cardiac output
sometimes observed with late onset disease [ 94-98 ]. However, this association may
also be the result of confounders associated with both preeclampsia and birth of large
for gestational age infants (eg, obesity, impaired glucose tolerance) [ 99 ].
Abruptio placenta is infrequent (less than 1 percent) in women with mild preeclampsia,
but has been reported in 3 percent of those with severe disease [101 ]. (See "Placental
abruption: Clinical features and diagnosis" .)
Impaired placentation can lead to increased impedance to flow in the uterine arteries,
manifested by elevation of the pulsatility index accompanied by uterine artery notching
on uterine artery Doppler velocimetry. However, this finding is neither sensitive nor
specific for preeclampsia. (See "Prediction of preeclampsia", section on 'Uterine artery
Doppler velocimetry' .)
Initial assessment for proteinuria is commonly performed by dipping a paper test strip
into a fresh clean voided midstream urine specimen. Proteinuria +1 on dipstick
should be confirmed by quantitative assessment (24 urine collection or
protein:creatinine ratio). (See "Evaluation of proteinuria in pregnancy" .)
Therefore, the history and physical examination should evaluate the patient for:
Nausea, vomiting
Oliguria
Dyspnea
Platelet count
Serum creatinine
Additional tests that can be informative include blood smear and serum lactate
dehydrogenase (LDH) and bilirubin concentrations. Microangiopathic hemolysis is
suggested by elevated LDH and indirect bilirubin levels and red cell fragmentation
(schistocytes or helmet cells) on peripheral blood smear (picture 2A-B ).
Hemoconcentration occurs in preeclampsia, but hemolysis, if present, can decrease the
hematocrit to normal or anemic levels.
Differential diagnosis
In this setting, a variety of factors can be helpful in establishing the likely diagnosis:
Normally, plasma uric acid concentration decreases in early pregnancy and then
increases [ 106,107 ]. Preeclampsia is typically associated with a rise in the plasma
urate level to above 5.5 to 6 mg/dL (327 micromol/L) [ 108 ]. The plasma urate
concentration tends to remain below this level in preexisting hypertension, unless the
patient is taking diuretics or has superimposed preeclampsia [ 107 ].
Significant clues to the diagnosis of severe preeclampsia are the presence of systemic
manifestations of the disorder, such as thrombocytopenia, increased serum levels of
aminotransferases, and visual symptoms ( table 2 ) [ 109 ]. Onset of disease in the
first half of pregnancy suggests exacerbation of underlying renal disease, rather than
preeclampsia.
AFLP, TTP, HUS, SLE Although preeclampsia/HELLP is the most common cause of
hypertension, thrombocytopenia, liver abnormalities, and renal abnormalities in
pregnant women, the following conditions should be considered and excluded, if
possible. Laboratory findings in these disorders are compared in the tables ( table 5A-
B ).
Acute fatty liver of pregnancy (AFLP). Low grade fever can be present in AFLP,
but does not occur in preeclampsia/HELLP. AFLP is associated with more
serious liver dysfunction: hypoglycemia and disseminated intravascular
coagulation are common features, while unusual inpreeclampsia/HELLP. AFLP
is also usually associated with more significant renal dysfunction compared
to preeclampsia/HELLP. (See "Acute fatty liver of pregnancy" .)
Basics topics (see "Patient information: Preeclampsia (The Basics)" and "Patient
information: High blood pressure and pregnancy (The Basics)" and"Patient
information: HELLP syndrome (The Basics)" )
Beyond the Basics topics (see "Patient information: Preeclampsia (Beyond the
Basics)" )
Platelet count
Serum creatinine
Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT)
REFERENCES
Observational data suggest that the decision to expedite delivery in the setting of
severe preeclampsia does not mandate immediate cesarean birth [ 9,10]. Cervical
ripening agents can be used prior to induction if the cervix is not favorable [ 11 ].
However, we feel that a prolonged induction and inductions with a low likelihood of
success are best avoided. Cesarean delivery is reasonable for women with severe
preeclampsia who are under 30 weeks of gestation and have a low Bishop score, given
the high frequency of nonreassuring fetal heart rate tracings and failure of the cervix to
dilate in this setting [ 11-13 ]. Only about one-third of preterm inductions result in
vaginal birth.
This trial showed that preeclamptic women benefited from early intervention,
without incurring an increased risk of operative delivery or neonatal
morbidity. The trial was not large enough to determine whether small
differences in newborn outcomes or induction between 36 and 37 weeks
might be statistically significant. A follow-up economic analysis of this trial
concluded induction was also less costly overall than expectant management
with monitoring [ 17 ]. Another follow-up analysis showed that an
unfavorable cervix was not a reason to avoid induction [ 18 ].
The optimum management for women with mild preeclampsia and stable maternal and
fetal conditions at 34 0/7 to 36 0/7 weeks remains uncertain; no randomized trials have
been performed in this population [ 19 ]. These pregnancies are generally managed
expectantly to enable further fetal growth and maturation. Progression of the disease
is generally slow and observational data show that many patients with late onset
disease will reach term with only mild disease. For patients managed expectantly,
delivery is indicated as soon as they develop signs or symptoms of
severe preeclampsia/eclampsia ( table 2 ) or at 37 weeks of gestation if the disease
does not progress to this stage.
Patients should be told to call their health care provider immediately if they develop
severe or persistent headache, visual changes, right upper quadrant or epigastric pain,
nausea or vomiting, shortness of breath, significant weight gain over one to two days,
or decreased urine output [ 27 ]. As with any pregnancy, decreased fetal movement,
vaginal bleeding, abdominal pain, rupture of membranes, or uterine contractions
should be reported immediately, as well.
The value of other tests is less clearly defined. A rising hematocrit can be useful to look
for hemoconcentration, which suggests contraction of intravascular volume and
progression to more severe disease, while a falling hematocrit may be a sign of
hemolysis. An elevated serum indirect bilirubin concentration is a better sign of
hemolysis, although an elevated LDH may also be a marker of severe disease or HELLP
syndrome. Hemolysis can be confirmed by observation of schistocytes and helmet cells
on a blood smear ( picture 1A-B ). (See "HELLP syndrome" .)
Since several clinical studies have shown that neither the rate of increase nor the
amount of proteinuria affects maternal or perinatal outcome in the setting of
preeclampsia [ 5-8 ], repeated 24-hour urinary protein estimations are not useful once
the threshold of 300 mg/24 hours for the diagnosis of preeclampsia has been
exceeded. Serum creatinine alone can be used to monitor renal function. When
required, quantification of protein excretion can be performed using a 24-hour
collection or protein-to creatinine ratio on a random specimen. (See "Expectant
management of severe preeclampsia" .)
Sodium restriction below the recommended daily intake and diuretics have no role in
routine therapy [ 28-30 ]. Although intravascular vascular volume is reduced, a
randomized trial showed that plasma volume expansion did not improve maternal or
fetal outcome [ 31 ].
Evaluation of umbilical artery Doppler indices is also useful, as the results help in
optimal timing of delivery. In a meta-analysis of 16 randomized trials in high risk
pregnancies, knowledge of umbilical artery Doppler velocimetry results was associated
with a 29 percent reduction in perinatal death (RR 0.71, 95% CI 0.52-0.98, 10,225
babies, 1.2 versus 1.7 percent; number needed to treat 203, 95%CI 103- 4352),
primarily in pregnancies complicated by preeclampsia and/or growth restriction. The
frequency of assessment depends on the findings; weekly assessment is reasonable
when Doppler indices are normal. (See "Doppler ultrasound of the umbilical artery for
fetal surveillance", section on 'Clinical effectiveness' and "Doppler ultrasound of the
umbilical artery for fetal surveillance", section on 'Guidelines for clinical practice' .)
Assessment of fetal growth Early fetal growth restriction may be the first
manifestation of preeclampsia and is a criterion of severe disease. We suggest
sonographic estimation of fetal weight be performed to look for growth restriction and
oligohydramnios at the time of diagnosis of preeclampsia and then repeated every
three weeks if the initial examination is normal [ 27 ]. If fetal growth is suboptimal, the
frequency can be increased. (See "Fetal growth restriction: Evaluation and
management", section on 'Serial fetal weight assessment' and "Doppler ultrasound of
the umbilical artery for fetal surveillance" .)
INTRAPARTUM MANAGEMENT
The major concerns associated with general anesthesia (for cesarean delivery) are a
transient spike in blood pressure during intubation (response to noxious stimuli),
hypotension (from reduction in cardiac output and systemic vascular resistance), and
difficult or failed intubation because of oropharyngeal edema. (See "Airway
management of pregnant women at delivery" .)
Given these issues, early patient assessment by the anesthesia team is desirable.
Dosing Although published dosage regimens for magnesium sulfate vary widely
(loading dose of 4 to 6 grams intravenously and maintenance dose of 1 to 3 grams per
hour), the most common regimen, and the one that we use, is a loading dose of 6
grams intravenously over 15 to 20 minutes followed by 2 grams per hour as a
continuous infusion [ 1,38,43,46 ]. An alternative regimen is 5 grams intramuscularly
into each buttock (total of 10 grams) followed by 5 grams intramuscularly every four
hours. However, this method is associated with more side effects, particularly pain at
the injection site.
There does not appear to be a clear threshold concentration for insuring the prevention
of convulsions, although a therapeutic range of 4.8 to 8.4 mg/dL(2.0 to
3.5 mmol/L) has been recommended based on retrospective data [ 47 ]. Loading doses
less than 6 grams are more likely to result in subtherapeutic magnesium levels (less
than 4.5 mg/dL) [ 43,48 ].
Since magnesium sulfate is excreted by the kidneys, dosing should be adjusted in
women with renal insufficiency (defined as a serum creatinine greater than
1.0 mg/dL). Such women should receive a standard loading dose (since their volume of
distribution is not altered), but a reduced maintenance dose (1 gram per hour or no
maintenance dose if the serum creatinine is greater than 2.5 mg/dL) and close
monitoring of their serum magnesium level every six hours.
The maintenance phase is given only if a patellar reflex is present (loss of reflexes
being the first manifestation of symptomatic hypermagnesemia), respirations exceed
12 per minute, and the urine output exceeds 100 mL per four hours. (See "Symptoms
of hypermagnesemia" .) Following serum magnesium levels is not required if the
woman's clinical status is closely monitored for evidence of potential magnesium
toxicity (see 'Complications and side effects' below). The maintenance dose should be
decreased if there is clinical evidence of magnesium toxicity.
Although magnesium sulfate is a weak tocolytic, labor duration does not appear to be
affected by magnesium sulfate administration [ 57 ]. The risk of postpartum
hemorrhage, possibly related to uterine atony from magnesium's tocolytic effects, was
slightly increased in one trial [ 42 ].
Magnesium freely crosses the placenta; as a result, the cord blood concentration
approximates the maternal serum concentration. Maternal therapy causes a decrease
in baseline fetal heart rate, which generally remains within the normal range, and a
decrease in fetal heart rate variability, which may be absent or minimal [ 58 ].
Antenatal fetal assessment test results (eg, biophysical profile score and nonstress test
reactivity) are not significantly altered [ 59 ].
Magnesium therapy results in a transient reduction of total and ionized serum calcium
concentration due to rapid suppression of parathyroid hormone release [ 60 ]. Rarely,
hypocalcemia becomes symptomatic (myoclonus, delirium, ECG abnormalities).
(See "Symptoms of hypermagnesemia", section on 'Hypocalcemia' .) Cessation of
magnesium therapy will restore normal serum calcium levels. However, calcium
administration may be required if symptoms are present ( calcium gluconate 1 gram
intravenously over 5 to 10 minutes). (See "Causes and treatment of
hypermagnesemia" .)
Recurrence The recurrence risk varies with the severity and time of onset of the
acute episode [ 65 ]. Women with early onset, severe preeclampsia are at greatest risk
of recurrence (as high as 25 to 65 percent) [ 66-68 ]. The risk is much lower (5 to 7
percent) in women who had mild preeclampsia during the first pregnancy, versus less
than 1 percent in women who had a normotensive first pregnancy (does not apply to
abortions) [ 66,69-74 ]. The occurrence of preeclampsia in future pregnancies is best
illustrated by the following prospective study:
A large prospective cohort study (Avon Longitudinal Study of Parents and Children,
ALSPAC) published after these reviews reported similar findings [ 80 ].
Women with early onset/severe preeclampsia with preterm delivery are at highest risk
of cardiovascular disease later in life, including during the premenopausal period
( table 3 ) [ 81 ]. In contrast, mild preeclampsia occurring late in gestation does not
appear to be associated with a high risk of remote cardiovascular disease [ 82 ]. The
stronger association between cardiovascular disease and preterm preeclampsia
suggests that the pathogenesis of early versus late preeclampsia may be different.
Although women who went on to develop ESRD may have had subclinical renal disease
during pregnancy, it is also possible that as yet undefined risk factors predisposed
these women to both preeclampsia and ESRD. It is less likely that preeclampsia
damages the kidney, thereby initiating a process of chronic deterioration.
Here are the patient education articles that are relevant to this topic. We encourage
you to print or e-mail these topics to your patients. (You can also locate patient
education articles on a variety of subjects by searching on patient info and the
keyword(s) of interest.)
Basics topics (see "Patient information: Preeclampsia (The Basics)" and "Patient
information: High blood pressure and pregnancy (The Basics)" and"Patient
information: HELLP syndrome (The Basics)" )
Beyond the Basics topics (see "Patient information: Preeclampsia (Beyond the
Basics)" )