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Cardiopulmonary Complications of Pre-eclampsia
Samuel Thomas Bauer, MD, and Kirsten Lawrence Cleary, MD, MSCE
Pre-eclampsia affects 3 to 8% of all pregnancies. In the USA, pre-eclampsia remains a
leading cause of maternal morbidity and mortality, comprising 17% of maternal deaths in
advanced gestations in 1999. The pathophysiologic changes associated with pre-eclampsia
can have a profound impact on the uteroplacental unit and fetal and neonatal outcome.
Equally important are the adverse effects on the maternal hematologic, cardiovascular and
pulmonary, neurologic, renal, and gastrointestinal system. This article aims to review
complications of pre-eclampsia as they impact on the cardiovascular and pulmonary
systems.
Semin Perinatol 33:158-165 © 2009 Elsevier Inc. All rights reserved.
KEYWORDS acute respiratory distress syndrome, cardiovascular disease, peripartum cardiomyopathy, pre-eclampsia
Pre-Eclampsia
and the Physiology
of Cardiovascular System
A
lterations of the normal cardiovascular physiology occur
in patients with pre-eclampsia. These are related to the
following: (1) cardiac preload, which is affected by hemoconcentration and pathologically diminished hypervolemia of
pregnancy; (2) increased cardiac afterload caused by hypertension; and (3) endothelial activation with extravasation
into the extracellular space, especially the pulmonary system,
which places patients at risk for pulmonary edema.1
Hemodynamic cardiovascular changes often occur before
the onset of hypertension. Bosio and colleagues conducted a
longitudinal study of 400 primigravidas, who were monitored throughout pregnancy using Doppler echocardiography. Gestational hypertension and pre-eclampsia developed
in 24 (6%) and 20 (5%) women, respectively. Compared
with normotensive controls, women who had pre-eclampsia
had significantly elevated cardiac output before clinical diagnosis, but total peripheral resistance was not significantly
different during this latent phase. After the diagnosis of preeclampsia was made, there was a marked reduction in cardiac
output and increase in peripheral resistance. In contrast,
Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY.
Address reprint requests to Samuel Thomas Bauer, MD, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Columbia University Medical Center, 622 West 168th Street, PH 16-66, New
York, NY 10032. E-mail: [email protected]
158
0146-0005/09/$-see front matter © 2009 Elsevier Inc. All rights reserved.
doi:10.1053/j.semperi.2009.02.008
women with gestational hypertension had no such hemodynamic crossover and maintained hyperdynamic circulation
throughout pregnancy.2
Terrone and colleagues at the University of Mississippi
studied and categorized cardiopulmonary morbidity in 979
patients with severe pre-eclampsia/hemolysis, elevated liver
enzymes, and low platelet count (HELLP) syndrome.3 Cardiopulmonary morbidity was categorized as congestive heart
failure, pulmonary edema or effusion, acute lung injury/
acute respiratory distress syndrome (ARDS), mechanical ventilation, or a cardiopulmonary event (Table 1). Cardiopulmonary morbidity occurred in 7.6% of study patients. Patients
with class 1 HELLP syndrome, defined as severe thrombocytopenia with a perinatal platelet nadir ⱕ50,000/␮L, a total
serum lactate dehydrogenase of ⱖ600 IU/L, and serum
transaminase level of ⱖ70 IU/L either as aspartate amino
transferase and/or alanine aminotransferase, more frequently
encountered cardiopulmonary morbidity (P ⬍ 0.003) than
did any other group with an odds ratio of 2.2 (95% CI 1.4,
3.7). These patients were more likely to experience acute
lung injury/ARDS and/or require continuous positive airway
pressure/mechanical ventilation. As a group, preeclamptic
patients with cardiopulmonary complications were more
likely to have cesareans (11% vs. 6%, P ⫽ 0.019), have low
birth weight neonates (1366 ⫾ 700 vs. 1734 ⫾ 892 g, P ⫽
0.021), sustain higher peak postpartum blood pressures (P ⬍
0.001), and have more abnormal laboratory values indicative
of multisystem disease, compared with patients without cardiopulmonary complications. Patients with pre-eclampsia
and concurrent cardiopulmonary morbidity took almost
twice as long to achieve diuresis as comparison patients (22 ⫾
23 vs. 12 ⫾ 11 h, P ⬍ 0.001).3
Cardiopulmonary complications of PE
159
Table 1 Comparison of Cardiopulmonary Morbidity in Patients With HELLP Syndrome and in Patients With Severe Pre-Eclampsia
Without HELLP Syndrome3
Complication
Class I
HELLP
Class II
HELLP
Class III
HELLP
Severe
Pre-Eclampsia
P
Value
Congestive heart failure
Pulmonary edema/effusion
Acute lung injury/ARDS
Continuous positive airway pressure/mechanical ventilation
Cardiopulmonary arrest
Any cardiopulmonary event
7
11
12
14
1
26 (12.3%)
4
5
3
7
1
13 (4.3%)
8
10
4
4
1
23 (8.3%)
3
7
2
4
1
12 (6.2%)
0.365
0.149
0.004
0.004
*
0.008
*P value not reported because of insufficient data.
During normal pregnancy, plasma and red cell volumes
increase by approximately 42% and 24%, respectively. The
total blood volume of an average size woman will increase
from approximately 3500 mL in the nonpregnant state to
near 5000 mL toward the end of the third trimester of pregnancy.4 When compared to normal nonpregnant subjects,
patients with pre-eclampsia demonstrate increased vascular
resistance, decreased circulatory volume, and decreased peripheral perfusion. Plasma volume reduction and hemoconcentration remains a hallmark of pre-eclampsia and occurs in
proportion to the severity of the disease process.5 In the
1980s, Rafferty and Berkowitz studied 3 patients with severe
pre-eclampsia using thermodilution tip pulmonary artery
catheters during cesarean section under general endotracheal
anesthesia. The left ventricular stroke work indexes (LVSWI) of
these patients were higher than those of normal nonpregnant
women, but there was no evidence of myocardial depression in
either cardiac index or the LVSWI-pulmonary capillary wedge
pressure relationship. Pulmonary arteriolar resistance was
found to be within or below the normal nonpregnant range,
suggesting that the pulmonary vasculature is not involved in a
primary vasospastic process in severe pre-eclampsia. At delivery, a rise in cardiac index and mean pulmonary capillary wedge
pressure occurred. The pulmonary capillary wedge pressure
was higher in the postpartum period than before delivery, potentially representing an increase in circulating blood volume.6
Benedetti et al. substantiated these findings when they noted an
increase in LVSWI and hyperdynamic ventricular function in 10
patients with severe pre-eclampsia and pulmonary artery catheters during labor.7
Cotton and colleagues later performed right-heart catheterization in 45 women with severe pre-eclampsia or eclampsia. Most patients had high-normal or elevated systemic vascular resistance indexes, hyperdynamic left ventricular
function, normal or increased pulmonary capillary wedge
pressure, and low central venous pressure (Table 2).8
In the setting of chronic hypertension with superimposed
pre-eclampsia, systemic vascular resistance and left heart filling pressures are increased. This leads to a decrease in cardiac
output and an increase in pulmonary vascular hydrostatic
pressure, which culminates in the development of pulmonary edema. An additional feature that may predispose to the
development of pulmonary edema in the setting of preeclampsia is an increase in capillary leak and capillary fluid
extravasation secondary to vascular endothelial damage. Re-
searchers measure capillary leak by measuring the interstitial
fluid from subcutaneous tissue in the thorax and ankle by
implanted wicks and interstitial fluid hydrostatic pressure.9
Pulmonary artery catheter research in pregnancy consists
of retrospective data: case reports, small series, or reviews.
No randomized trials support their routine use in women
with severe pre-eclampsia. Most of the reports primarily describe hemodynamic parameters and fluid status of preeclampsia and do not mention particular complications.
Given the known complications of pulmonary artery catheters, including cardiac arrhythmias, pneumothorax, hemothorax, neurologic injury, and pulmonary hemorrhage, we
do not recommend invasive monitoring for routine clinical
cases. However, invasive hemodynamic monitoring may
prove beneficial in women with pre-eclampsia and severe
cardiac disease, severe renal disease, refractory hypertension,
oliguria, or pulmonary edema.10,11 Pulmonary artery catheters aided in clinical management decisions in 93% of cases of
severe pre-eclampsia complicated by renal failure or pulmonary edema in a small, retrospective series of 17 women with
eclampsia. The pulmonary artery catheter was considered
subjectively helpful if the initial readings (central venous
pressure and pulmonary capillary wedge pressure) clarified
patients’ fluid status and helped guide decision-making.
Catheter placement was not helpful if the initial readings
were unobtainable, inconsistent, or not used to influence or
determine decision-making.12
Table 2 Hemodynamic Findings in Severe Pre-Eclampsia8
Cardiac output is variable
Mean arterial pressure is elevated; systemic vascular
resistance is normal (early) or elevated (late)
Central venous pressure is usually low to normal and does
not correlate with pulmonary capillary wedge pressure
Pulmonary hypertension and pulmonary vascular
resistance are not present, but low pulmonary artery
pressure may occur in the presence of hypovolemia
Pulmonary capillary wedge pressure may be low, normal,
or high
Oliguria may not reflect volume depletion
Ventricular function is usually hyperdynamic but may be
depressed in the presence of marked elevation in
systemic vascular resistance
Colloid oncotic pressure is usually low
160
If pulmonary edema remains refractory to initial management or is accompanied by persistent oliguria, insertion of a
pulmonary artery catheter and transfer to an intensive care
unit where mechanical ventilatory support could be provided may be considered.13
Pulmonary Edema
Pulmonary edema is the most common cardiopulmonary
complication of pre-eclampsia and refers to an excessive accumulation of fluid in the pulmonary interstitial and alveolar
spaces. The development of pulmonary edema is usually
multifactorial. According to the Starling equation, any factor
that results in a reduction in colloid osmotic pressure, an
increase in capillary permeability, or an increase in intravascular hydrostatic pressure will lead to extravasation of fluid
from the vasculature and predispose to the development of
pulmonary edema.14 The underlying physiological changes
in the maternal cardiovascular system, including increased
plasma blood volume, cardiac output, heart rate, and capillary permeability and a decrease in plasma colloid osmotic
pressure, are exaggerated in pre-eclampsia and predispose
women to develop pulmonary edema. Plasma colloid osmotic pressure decreases from around 22 mm Hg at term to
16 mm Hg after delivery, in normal pregnancies, and from 18
mm Hg at term to 14 mm Hg postpartum in pregnancies
complicated by pre-eclampsia. The reduction in postpartum
colloid osmotic pressure may result from excessive blood
loss, fluid shifts secondary to increased capillary permeability, especially in pregnancies complicated by pre-eclampsia.
Such changes help to explain why 70%-80% of cases of pulmonary edema in the setting of pre-eclampsia develop after
delivery.15
Sibai described a series of 37 severe preeclamptic or
eclamptic patients with pulmonary edema in which the incidence of pulmonary edema was significantly higher in older
patients (P ⬍ 0.0001) and in multigravidas (P ⬍ 0.05).
Eleven (30%) had antepartum pulmonary edema with 10
(90%) of the 11 having pre-existing chronic hypertension.
Twenty-six (70%) had postpartum onset of pulmonary
edema with an average onset at 71 hours postpartum.16 In a
retrospective cohort study of California birth records, Gilbert
and colleagues reviewed 29,842 pregnant women with
chronic hypertension. As compared to nonchronic hypertensive patients, pulmonary edema was increased: (OR 5.2; 95%
CI 3.9, 6.7).17
Clinicians have often questioned whether magnesium sulfate, administered to preeclamptic women for seizure prophylaxis, leads to pulmonary edema. Yeast and colleagues
measured the effect of intravenous magnesium sulfate administered for preterm labor or seizure prophylaxis on colloid osmotic pressure and the risk for pulmonary edema in
294 pregnant women. Only 4 of the 294 women developed
pulmonary edema, and all 4 had low colloid osmotic pressure
in the setting of severe pre-eclampsia. Magnesium sulfate did
not significantly change colloid osmotic pressure and does
not pose a significantly increased risk for developing pulmonary edema.18
S.T. Bauer and K.L. Cleary
Pulmonary edema is a clinical diagnosis characterized by
worsening dyspnea and orthopnea along with signs of respiratory compromise (tachypnea, auditory crackles and rales,
and hypoxemia). Arterial blood gas and chest X-ray may
assist in the diagnosis. On postanterior and lateral chest X-ray
films, the early signs of pulmonary edema (interstitial edema)
are Kerley B lines, which are horizontal lines seen laterally in
the lower zones reaching the lung edge. As the edema
progresses, alveolar edema is observed in a “butterfly-like”
pattern, which is characterized by the central predominance
of shadows with a clear zone at periphery lung lobes. Cardiac
enlargement characterizes progression to cardiac failure. Pulmonary edema may resemble the initial stages of ARDS.19 In
select patients, electrocardiography, echocardiography, spiral computed tomographic imaging, ventilation/perfusion
scan, or pulmonary arteriography may be necessary to exclude other causes of cardiopulmonary compromise, such as
pulmonary embolism, pneumonia, and cardiomyopathy.
Two-dimensional and Doppler echocardiography provide
an additional diagnostic modality for patient with preeclampsia complicated by pulmonary edema. Desai and colleagues diagnosed impaired left ventricular systolic function
in 4 of 16 (25%) patients with pre-eclampsia and pulmonary
edema. In the remaining 12 patients with preserved systolic
function, left ventricular diastolic filling abnormalities were
demonstrated in a significant proportion compared to control hypertensive and normotensive groups.20
Mabie and colleagues evaluated the role of echocardiography in determining the cause of pulmonary edema in pregnancy. Forty-five pregnant or recently postpartum women
admitted to an obstetrical intensive care unit with pulmonary
edema during a 6-year period were followed prospectively.
In 21 patients (47%), echocardiography demonstrated clinically unsuspected findings, which altered the long-term
management in 16. Because clinical and roentgenographic
findings do not accurately differentiate patients with respect
to the presence and type of cardiac dysfunction, we recommend echocardiography to evaluate all pregnant women with
pulmonary edema.21
Prompt diagnosis of pulmonary edema and intervention
are critical. The morbidity and mortality associated with preeclampsia complicated by pulmonary edema have been
greatly reduced by accurately assessing cardiovascular function and aggressive treatment. The presence of hypertension,
proteinuria, and pulmonary edema satisfies the criteria for
severe pre-eclampsia and precludes further conservative
management. The diagnosis of severe pre-eclampsia requires
immediate hospitalization in labor and delivery. Intravenous
magnesium sulfate prevents seizures and antihypertensive
medications lower severe levels of hypertension (systolic
pressure greater than 160 mm Hg and/or diastolic pressure of
at least 110 mm Hg). Patients with pulmonary edema deliver
within 24-48 hours irrespective of fetal gestational age.22
Medical therapies to treat pulmonary edema should be
optimized to expedite treatment results. Furosemide (Lasix)
can be administered intravenously as a single dose of 10-40
mg over 2 minutes to promote diuresis. Bladder catheterization allows for accurate measurement of urine output. While
Cardiopulmonary complications of PE
most patients will respond to initial diuresis therapy, if adequate response is not seen within 30-60 minutes, the dose
should be increased to 40-60 mg administered by slow intravenous injection to a maximum of 120 mg in 1 hour. Electrolytes should be monitored closely and repleted as indicated. Morphine sulfate can be administered intravenously as
needed both for pain as well as in an attempt to reduce the
adrenergic vasoconstrictor stimuli to the pulmonary arteriolar and venous beds. As with the management of all parturients with pre-eclampsia, sodium and water should be modestly restricted, and maternal fluid balance should be strictly
monitored. Oxygen saturation can be monitored using a
pulse oximeter, and oxygen supplementation using a nonrebreather facemask can be used to treat maternal hypoxemia. In addition to these standard measures, it is appropriate to follow the patient’s blood pressure, electrocardiogram,
and fetal heart rate tracing. Afterload reduction using vasodilators may be necessary, especially in parturients with
chronic hypertension and superimposed pre-eclampsia. Because most obstetrical patients have normal left ventricular
systolic function, inotropic support is rarely necessary.13
Acute Respiratory
Distress Syndrome
ARDS is a form of respiratory failure characterized by acute
hypoxemia and increased alveolar-capillary permeability resulting from diffuse and ongoing pulmonary inflammation.23
Patients experience acute hypoxemic respiratory failure, often accompanied by dyspnea, tachypnea, cyanosis, and
tachycardia. Diffuse bibasilar crackles or wheezing can be
appreciated on auscultation of the chest. Minimal evidence
exists regarding the management of ARDS in pregnancy;
mortality remains high, and few strategies have shown a mortality benefit. The treatment of ARDS in pregnancy is often
extrapolated from studies performed in the general ARDS
patient population, with consideration given to the normal
physiological changes of pregnancy.
Definitions vary for pregnancy-related ARDS, including
ARDS during pregnancy or within 1 week or 1 month postpartum. Expanding this definition to several weeks postpartum may be appropriate, as it can take up to 6 weeks postdelivery for most of the physiological changes of pregnancy
to resolve.24
Pre-eclampsia complicated by HELLP syndrome, pulmonary edema, and/or cardiopulmonary disease can advance to
pregnancy-related ARDS. In a series of 83 obstetrical patients
with ARDS from all causes, the antepartum mortality rate was
23% and the postpartum mortality rate was 50%.25
The effect of maternal ARDS on neonatal outcomes is not
well studied, but high rates of fetal death, spontaneous preterm labor, and non-reassuring fetal heart rate tracing are
reported. In a series of 10 antepartum patients in the third
trimester ventilated for ARDS, only 5 of the neonates survived intact after delivery.24 Spontaneous preterm labor and
delivery was reported in 6 patients. Fetal heart rate abnormalities were reported in 6 of these pregnancies and occurred
161
within 4 days of admission. Of the 4 infants who did not
survive intact, 2 suffered perinatal asphyxia, 1 suffered perinatal asphyxia and cerebral palsy, and 1 suffered perinatal
death.
Respiratory support provides the cornerstone to management of ARDS in pregnancy, especially as respiratory alkalosis develops. Although a Pao2 of 55 mm Hg and an Sao2 of
88% would be tolerated in the general population, adequate
fetal oxygenation requires a Pao2 of ⱖ70 mm Hg, which
corresponds to a maternal Sao2 of about 95%.24 The broad
goals of ventilatory support in a pregnant woman with ARDS
are no different from the general population, namely, to manage blood-gas variables while avoiding ventilator-associated
lung injury. Likewise, the clinical criteria for intubating a
pregnant patient remain the same and include increased
work of breathing, mental status deterioration, hemodynamic instability, and inability to protect the airway or manage secretions.26
Little literature exists to guide the decisions on the mode of
delivery in patients with ARDS. A small retrospective study
suggests that cesarean delivery may improve the maternal
status in ventilated women in late pregnancy that have ARDS
but are clinically stable.24 Other studies have not supported
an improvement.21 Pregnant women with ARDS may not
tolerate a vaginal delivery due to increased oxygen consumption. Cesarean delivery results in larger and more rapid fluid
shifts and blood loss than with vaginal delivery and may
present a greater physiological stress. Until further data are
available, the decision for a mode of delivery should be based
on standard obstetrical indications. Attempts should be made
to optimize maternal oxygenation and pain control during
vaginal deliveries.27
Although ARDS during pregnancy is uncommon, when it
does occur, optimum management requires multidisciplinary care from maternal-fetal medicine, critical care medicine, obstetrical anesthesiology, pulmonology, and neonatology.
Peripartum Cardiomyopathy
Peripartum cardiomyopathy (PPCM) affects patients late in
pregnancy or in the early postpartum period. It is an infrequent complication of pre-eclampsia, but a history of preeclampsia can be found in up to 70% of those who develop
PPCM. The 4 following criteria are needed to meet the definition of peripartum cardiomyopathy: (1) development of
cardiac failure in the last month of pregnancy or within 5
months of delivery; (2) absence of an identifiable cause for
the cardiac failure; (3) absence of recognizable heart disease
before the last month of pregnancy; (4) left ventricular systolic dysfunction (for example, left ventricular ejection fraction (EF) below 45%).28 The etiology remains unclear, but
risks factors include multiple pregnancy, pre-eclampsia,
multiparity, and advanced maternal age. Pre-eclampsia is associated with peripartum cardiomyopathy; however, peripartum cardiomyopathy is an infrequent complication of
pre-eclampsia.29
S.T. Bauer and K.L. Cleary
162
Etiology
The etiology of peripartum cardiomyopathy remains unknown despite significant research. No distinct hormonal
disorder has been identified in patients with PPCM, even
though estrogen, progesterone, and prolactin have significant effects upon the cardiovascular system. There are multiple factors, including hemodynamic changes of pregnancy,
which may contribute to the physiological process. Blood
volume and cardiac output increase during pregnancy,
which results in transient left ventricular remodeling and
hypertrophy. These changes may produce an exaggerated
decrease in left ventricular systolic function in women who
develop peripartum cardiomyopathy. The hemodynamic
stress of gestational hypertension and acute pre-eclampsia is
more common in women with peripartum cardiomyopathy
and may contribute to the development of heart failure.30
The clinical course of peripartum cardiomyopathy varies,
with 50%-60% of patients showing complete or near-complete recovery of clinical status and cardiac dysfunction, usually within the first 6 months postpartum. Maternal mortality
rate is reported to be 25%-50%, but more recent studies
show a 95% 5-year survival rate. Women with residual cardiac dysfunction postpartum should be counseled against
future pregnancy given associated risk for worsening left ventricular function.31
Elkayam and colleagues reviewed data obtained from 123
women with a history of cardiomyopathy diagnosed during
pregnancy and/or the postpartum period. Peripartum cardiomyopathy patients had a mean age of 31 ⫾ 6 years and were
mostly Caucasian (67%). Common associated conditions
were hypertension/pre-eclampsia (43%), tocolytic therapy
(19%), and twin pregnancy (13%). Left ventricular EF at the
time of diagnosis was 29% ⫾ 11% and improved to 46% ⫾
14% (P ⬍ 0.0001) at follow-up. Normalization of left ventricular EF occurred in 54% and was more likely in patients
with left ventricular EF ⬎30% at diagnosis. Maternal mortality was 9%.32
Witlin and colleagues reviewed 28 patients without an
antecedent history of heart disease who were diagnosed with
peripartum cardiomyopathy. Pre-eclampsia was identified in
19 of the 28 (68%) patients. The unique hemodynamic
stresses of pregnancy in combination with a history of preeclampsia can unmask previously undiagnosed cardiomyopathy in otherwise medically stable women.33
Habli and colleagues were the first to report a correlation
between left ventricular EF in women with peripartum cardiomyopathy at initial presentation and at subsequent pregnancy and long-term outcome. The patients were categorized
by their initial EF into EFs of 25% or less and EF of greater
than 25%. Among 28 patients with EF of 25% or less, 16
(57%) had end-stage cardiac disease. One had a transplant
and 15 were on a transplant list. All 16 had a baseline EF of
25% or less at index pregnancy: 4 had improved (EF ⬎40%)
at interval follow-up and 3 at last follow-up available.
Women with a history of postpartum cardiomyopathy had a
higher rate of progression of symptoms of heart failure in a
subsequent pregnancy. These findings offer providers with
important counseling information for patients with an obstetrical history complicated by peripartum cardiomyopathy.34
Ischemic Heart
Disease—Myocardial Infarction
Myocardial infarction associated with pregnancy is a rare
event, usually related to maternal risk factors for ischemic
heart disease, such as hypertension, diabetes mellitus, and
coronary atherosclerosis. However, a mechanism of coronary
spasm has been suggested to be a cause of myocardial infarction in patients with normal coronary arteries or in those with
minimal nonobstructive coronary artery disease, especially
infarction related to pre-eclampsia, after administration of
ergot alkaloids, bromocriptine, oxytocin, and prostaglandin.
Early diagnosis of acute myocardial infarction in pregnancy is
often hindered by the normal changes of pregnancy and low
level of suspicion.
Epidemiology
The incidence of myocardial infarction in women of reproductive age is less than 1% and approximately 150 cases of
myocardial infarction during pregnancy have been documented in the literature worldwide.35 Despite the high frequency of hypertensive disease during pregnancy, little research has assessed long-term sequelae. The Royal College of
General Practitioners’ oral contraception study demonstrated
that women with a recorded diagnosis of pre-eclampsia had
nearly 3 times the risk of myocardial infarction as non-preeclamptic women.36 Hannaford and colleagues reviewed the
data from this study and found that parous women with a
history of pre-eclampsia had a statistically significant increased risk of ischemic heart disease and that increases were
seen in the 3 following major subcategories: (1) acute myocardial infarction; (2) chronic ischemic heart disease; and (3)
angina pectoris. Compared with parous women with no history of pre-eclampsia, those who had experienced preeclampsia had a significantly increased risk of hypertensive
disease, acute myocardial infarction, chronic ischemic
heart disease, angina pectoris, and ischemic heart disease
(Table 3).37
Women with a history of hypertension in pregnancy are at
an increased risk for ischemic heart disease compared with
the general population. In a population-based study of 7543
Table 3 Incidence of Vascular Disease in Parous Women With
and Without a Preceding History of Pre-Eclampsia41
Condition
Hypertensive disease
Acute myocardial infarction
Chronic ischemic heart
disease
Angina pectoris
All ischemic heart disease
Relative Risk Parous
Pre-Eclampsia (95% CI)
2.35 (2.08, 2.65)
2.24 (1.26, 2.16)
1.74 (1.06, 2.86)
1.53 (1.09, 2.15)
1.65 (1.26, 2.16)
Cardiopulmonary complications of PE
163
Table 4 Risk of Cardiac Disease After Pre-Eclampsia/Eclampsia
in Case-Control Studies49
Study
Weight (%)
Odds Ratio
(Random) 95% CI
Mann46
Rosenberg47
Croft36
Haukkamaa40
Total (95% CI)
6.47
42.30
32.00
19.23
100.00
3.60 (0.26, 50.70)
1.30 (0.65, 2.60)
3.60 (1.42, 9.10)
4.80 (1.21, 19.00)
2.47 (1.22, 5.01)
cases, Jonsdottir and colleagues reviewed the association between hypertension in pregnancy, pre-eclampsia, and eclampsia
and death rates from ischemic heart disease. The relative risk of
dying from ischemic heart disease was significantly higher
among eclamptic women (RR 2.61; 95% CI 1.11, 6.12) and
those with pre-eclampsia (RR 1.90; 95% CI 1.02, 3.52) than
those with hypertension alone. Parous women at the index
pregnancy had a 2-fold higher risk of dying from ischemic
heart disease than primigravid women (RR 2.05; 95% CI
1.19, 3.55; P ⫽ 0.01).38
Etiology and Pathophysiology
Fleming and colleagues have suggested that cardiac troponin
levels are elevated in women with pre-eclampsia.39 Fleming
examined troponin I levels in 69 women with pre-eclampsia
or gestational hypertension. There were 43 controls, 20 patients with gestational hypertension, and 6 patients with preeclampsia. Troponin I levels were significantly higher in the
gestational hypertensive groups compared with controls,
suggesting that coronary ischemic may be missed in patients
with hypertensive disorders in pregnancy, including preeclampsia.
Pre-Eclampsia Impacts
Long-Term Cardiovascular Health
Pre-eclampsia and coronary artery disease share common
risk factors for endothelial dysfunction and damage, such as
hypertension, diabetes, and obesity. The associated maternal
physiological changes from pre-eclampsia include increased
inflammatory markers, dyslipidemia, insulin resistance, endothelial dysfunction, and oxidative stress and are associated
with an increased risk for cardiovascular disease in later life.
A history of pre-eclampsia has been reported to be a risk
factor for several distinct cardiovascular conditions later in
life. Haukkamaa and colleagues40 reviewed the history of
hypertensive pregnancies and conventional risk factors in
141 relative young parous women with angiographically
documented coronary artery disease and showed that hypertension and pre-eclampsia were independent risk factors for
subsequent coronary artery disease, with adjusted odd ratios
of 5.2 (2.6, 11.0; P ⬍ 0.001) and 4.8 (95% CI 1.2, 19; P ⫽
0.03), respectively. Patients with coronary artery disease had
pre-eclampsia more often in the first or any subsequent pregnancy than did the control groups (17% vs. 3.0% and 1.8%,
P ⬍ 0.001).
With the recognition of hypertensive diseases of pregnancies as an etiology for subsequent heart disease later in life,
Wikstrom and colleagues investigated the question of
whether the risk of developing ischemic heart disease in later
life increases with severity of hypertensive disease during
pregnancy. After a review of 403,550 women in the Swedish
Medical Birth Register over a 9-year period with up to 15
years of follow-up, the adjusted incidence rate ratio for later
development of ischemic heart disease was 1.6 (95% CI 1.3,
2.0) when the first pregnancy was complicated by gestational
hypertension without proteinuria, 1.9 (95% CI 1.6, 2.2) for
mild pre-eclampsia, and 2.8 (95% CI 2.2, 3.7) for severe
pre-eclampsia. Women with hypertensive disease in both
pregnancies had an RR of 2.8 (95% CI 2.0, 3.9) compared
with women with 2 normal pregnancies.41
In a recent systematic review and meta-analysis,
McDonald and colleagues reviewed the existing literature to
determine if women with a history of pre-eclampsia/eclampsia are at increased risk of long-term cardiovascular sequelae.
Relative to women with uncomplicated pregnancies, women
with a history of pre-eclampsia/eclampsia had an increased
risk of subsequent cardiac disease in both the case-control
studies and the cohort studies, as well as an increased risk of
cardiovascular mortality. Women with a history of preeclampsia/eclampsia have approximately double the risk of
early cardiac and cardiovascular mortality (Tables 4 and 5).42
After a pregnancy complicated by pre-eclampsia, women
have an increased risk of vascular disease, including the following: hypertension after 14.1 years (3.70, 95% CI 2.70,
5.05), ischemic heart disease after 11.7 years (2.16, 95% CI
1.86, 2.52), stroke after 10.4 years (1.81, 95% CI 1.45, 2.27),
and venous thromboembolism after 4.7 years (1.79, 95% CI
1.37, 2.33). Overall mortality after pre-eclampsia was increased after 14.5 years: 1.49 (95% CI 1.05, 2.14).43
Irgens and colleagues demonstrated that mothers have increased cardiovascular morbidity and mortality risk after a
pregnancy complicated by pre-eclampsia. Women who had
pre-eclampsia had a 1.2-fold higher long-term risk of death
(95% CI 1.02, 1.37) than women who did not have preeclampsia. The risk in women with pre-eclampsia and a preterm delivery was 2.71-fold higher (1.99-3.68) than in
Table 5 Risk of Cardiac Disease After Pre-Eclampsia/Eclampsia
in Cohort Studies49
Study
Weight (%)
Relative Risk
(Random) 95% CI
Jonsdottir38
Hannaford37
Irgens44
Smith48
Kestenbaum49
Wilson50
Funai51
Kaaja52
Ray53
Wikstrom41
Total (95% CI)
8.51
16.10
11.11
8.39
11.19
4.43
13.04
4.78
10.62
11.82
100.00
2.12 (1.29, 3.49)
1.65 (1.26, 2.16)
2.12 (1.42, 3.16)
3.54 (2.14, 5.85)
2.53 (1.70, 3.77)
1.24 (0.58, 2.68)
3.07 (2.18, 4.33)
2.50 (1.20, 5.20)
2.85 (1.88, 4.32)
2.27 (1.56, 3.32)
2.33 (1.95, 2.78)
164
women who did not have pre-eclampsia and whose pregnancies went to term. In particular, the risk of death from cardiovascular causes among women with pre-eclampsia and a
preterm delivery was 8.12-fold higher (4.31, 15.33).44
Finally, a recent review has demonstrated that women
with severe, very early onset pre-eclampsia have an increased
risk of pre-eclampsia in future pregnancies. Women with
early onset severe pre-eclampsia exhibit more cardiovascular
risk factors. Gaugler-Senden and colleagues reviewed 20
women with early onset pre-eclampsia, before 24 weeks’ gestation. Cardiovascular risk profiles were compared to controls. Of the 20 women with history of early onset severe
pre-eclampsia, 17 women had 24 subsequent pregnancies, of
which 12 (50%) were complicated by pre-eclampsia. Severe
pre-eclampsia developed in five (21%) pregnancies. No perinatal deaths occurred. Women with a history of early onset
severe pre-eclampsia in a previous pregnancy had significantly more chronic hypertension than controls (55% vs.
10%, P ⫽ 0.002), as well as increased microalbuminuria (P ⬍
0.05).45
Women with early onset, recurrent, or severe pre-eclampsia appear to be at highest risk of cardiovascular disease later
in life, including during the premenopausal period. These
women may have unrecognized chronic hypertension, an
inherited thrombophilia, or other genetic or environmental
factors predisposing them to hypertension during and after
pregnancy.
Conclusions
Cardiovascular and cardiopulmonary complications due to
pre-eclampsia continue to affect thousands of women annually. Maternal morbidity and mortality from placental syndromes, including gestational hypertension and pre-eclampsia, probably arise from coexisting cardiovascular risk
factors. Cardiovascular complications can include peripartum cardiomyopathy, ischemic and coronary artery heart
disease, and pulmonary edema, acute lung injury, and acute
respiratory distress syndrome. Further research is needed to
understand the etiology of the increased risk of cardiopulmonary complications from pre-eclampsia and who pre-eclampsia/eclampsia might be incorporated into cardiopulmonary
and cardiovascular risk assessment along with other new risk
factors. Understanding the mechanism of cardiovascular diseases associated with pre-eclampsia is vital to the future of
women’s reproductive health.
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