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Pulmonary Arterial Hypertension
And Pregnancy: An Update
ELIZABETH A. M. FROST, MD
A
ll
Department of Anesthesia
Mount Sinai Medical Center
New York, New York
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Dr. Frost reports no relevant financial conflicts of interest.
A
ny cardiac disease
occurring during pregnancy
is challenging. As the number
and the complexity of cardiac cases
increase and maternal age advances, heart
disease has become the leading cause of maternal morbidity
and mortality in developing countries. Women with
s,
congenital heart disease comprise most of the cases,
owever,
although within this group mortality is infrequent. However,
ortic
pulmonary arterial hypertension (PAH) and severe aortic
dilatation remain high-risk conditions.1
Classification of Pulmonary Hypertension
Pulmonary hypertension is defined as an increase
in pressure in the pulmonary artery, veins, or capillaries in the lungs, leading to dyspnea, dizziness, fainting, and other symptoms, all of which are exacerbated
I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G
tion. Pulmoby exertion.
rtension can be
nary hypertension
severe, with markedly
decreased exercise tolerance and heart failure. First
identified by Dr. Ernst von Romberg, a German physician, in 1891,5 PH previously was divided into 2 categories, primary and secondary, based on identifiable
etiology. In 1998, the WHO proposed a clinical classification of PH based on similarities in pathophysiology,
clinical presentation, and therapeutic options, breaking PH into 5 distinct types: arterial, venous, hypoxic,
thromboembolic, and miscellaneous.6
In its 1973 meeting, the WHO divided primary PH
into arterial plexiform, veno-occlusive, and thromboembolic forms. At the 1998 meeting, the organization also
addressed the causes of secondary PH—those resulting from other medical conditions—and in 2003, the
d.
The World Health Organization (WHO) organized the
first international conference on pulmonary hypertension (PH) in 1973. At that time, no effective therapies
existed for the condition, and patients with primary or
idiopathic PH survived a median of less than 3 years
after diagnosis. Current treatments have more than
doubled the survival time, and more patients present
for surgery and anesthesia and survive to become pregnant. Nevertheless, pregnancy complicated by PH poses
risks to the mother that can prove fatal. At least 3 recent
articles have outlined the current treatment modalities
and the management of PH during pregnancy.2-4
A N E ST H E S I O LO GY N E WS S P E C I A L E D I T I O N • O C TO B E R 2 0 1 3
77
Pathophysiology
Table 1. The Venice 2003 Revised
Classification System for PAH
Group I. Pulmonary arterial hypertension
Idiopathic
Familial
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Associated with other diseases: collagen vascular disease (eg, scleroderma), congenital shunts
between the systemic and pulmonary circulation,
portal hypertension, HIV infection, drugs, toxins,
or other diseases or disorders
Co
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Associated with venous or capillary disease
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Pulmonary arterial hypertension (WHO Group I) is
a complex endothelial disorder that causes remodeling of the pulmonary arterial wall with endothelial
and smooth muscle proliferation. These changes are
consistent with overexpression of the vasoconstrictor endothelin-1 and a reduction in the vasodilators
nitric oxide (NO) and prostacyclin.8 Vasoconstriction of blood vessels connected to and within the
lungs, and altered vasodilation increase cardiac load.
Over time, the affected blood vessels fibrose, further
increasing pressure in the lungs and impairing blood
flow. The right ventricle hypertrophies (cor pulmonale develops), decreasing the ability of the heart to
pump blood through the lungs and ultimately causing
right heart failure (Figure). As blood flow through the
lungs decreases, the left side of the heart receives not
only less blood but blood that is poorly oxygenated,
decreasing the ability to supply sufficient oxygen to
the rest of the body, especially during physical activity.
Normal mean pulmonary pressure is 15 to 20 mm Hg;
pulmonary artery wedge pressure is 8 to 12 mm Hg;
and pulmonary vascular resistance (PVR) is less than
240 dyn/sec/cm5. Figures greater than these numbers
indicate PAH.
Pathogenesis of pulmonary venous hypertension
(PVH; WHO Group II) differs in that blood flow in the
lungs is unobstructed. Instead, the left heart fails to
pump blood efficiently, leading to pooling of blood in
the lungs, followed by pulmonary edema and pleural
effusions.
In hypoxic pulmonary hypertension (WHO Group
III), low levels of oxygen are thought to cause vasoconstriction of pulmonary arteries and a pathophysiology similar to PAH.
In chronic thromboembolic pulmonary hypertension
(WHO Group IV), vessels are blocked or narrowed by
blood clots. Again, the pathology is similar to that seen
with PAH. A further classification is made on functional
ability, characterized as Class 1 to 4 based on increasing physical limitations.
s
Group II. Pulmonary hypertension associated
with left heart disease
Atrial or ventricular disease
Valvular disease (eg, mitral stenosis)
Group III. Pulmonary hypertension associated
with lung diseases and/or hypoxemia
Chronic obstructive pulmonary disease, interstitial
lung disease
Sleep-disordered breathing, alveolar
hypoventilation
Chronic exposure to high altitude
Developmental lung abnormalities
Group IV. Pulmonary hypertension due to chronic
thrombotic and/or embolic disease
Pulmonary embolism in the proximal or distal
pulmonary arteries
Embolization of other matter, such as tumor cells
or parasites
Group V. Miscellaneous. Pulmonary hypertension
due to direct effect on the pulmonary vasculature of inflammatory diseases such as schistosomiasis,7 sarcoidosis, histiocytosis X, and fibrosing
mediastinitis.
Epidemiology
78
I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G
The overall prevalence of PH in the general population is unknown because of the heterogeneity of the
disease (Table 2).
The Centers for Disease Control and Prevention
(CDC) Pulmonary Hypertension Surveillance reported
changes in death rates from PH from 1980 to 2002 are
follows:
• The age-standardized death rates for the total US
population increased from 5.2 to 5.4 deaths per
100,000 population.
• The main increase in death rates was seen among
women, with 3.3 to 5.5 deaths per 100,000 population, and blacks, with 4.6 to 7.3 deaths per 100,000
population.
• The death rate in men decreased during this period,
from 8.2 to 5.4 deaths per 100,000 population.
d.
3rd World Symposium on Pulmonary Arterial Hypertension convened in Venice to modify the classification
based on new understanding of disease mechanisms.
The revised system developed by this group provides
the current framework for understanding PH. This system includes several improvements over the 1998 classification. Risk factor descriptions were updated, and
the classification of congenital systemic-to-pulmonary
shunts was revised (Table 1). A new classification of
genetic factors in PH was recommended but not implemented because available data were deemed inadequate.6 The classification does not include sickle cell
disease, another cause of PH. Infection with human herpesvirus 8, also associated with Kaposi’s sarcoma, has
been associated with PAH, suggesting that this virus
may play a role in its development.
Diagnosis
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Clinical signs in the early stages of PAH may be few.
A physical examination looks for typical signs of PH,
including altered heart sounds, such as a widely split
S2 or second heart sound, a loud P2 or pulmonic valve
closure sound (part of the second heart sound), (para)
sternal heave, possible S3 or third heart sound, and pulmonary regurgitation. Other signs include an elevated
jugular venous pressure, peripheral edema, ascites, hepatojugular reflux, and clubbing.3,8
Further procedures are required to confirm the presence of PH and exclude other diagnoses. These generally
include pulmonary function tests; blood tests to exclude
HIV, autoimmune diseases, and liver disease; electrocardiography; measurements of arterial blood gas; chest
x-rays followed by high-resolution computed tomography scanning if interstitial lung disease is suspected; and
ventilation-perfusion or V/Q scanning to exclude chronic
thromboembolic PH.
Transthoracic echocardiography (TTE) is used widely
as a screening tool for PH. Pulmonary arterial pressures
and right ventricular systolic pressure correlate well.
However, several factors such as severe lung disease,
premature ventricular contractions, and inaccurate estimates of right atrial pressure can lead to misdiagnosis.
Studies have found that TTE may overestimate pulmonary artery pressures compared with right heart catheterization (RHC).3 On the other hand, in about one-third
of patients, RHC may reveal more severe PH than is estimated from TTE. Thus, both under- and overestimating
may occur. However, PH does not mean PAH is present.
Therefore, clinicians must assess pulmonary artery occlusion pressures and PVR. Indeed, the diagnosis of PAH
must be confirmed with RHC in pregnant patients, given
the high morbidity and mortality associated with the
combination of the 2 conditions.8
Biopsy of the lung is usually not indicated unless the
PH is thought to reflect an underlying interstitial lung
disease. Lung biopsies carry risks for bleeding from high
intrapulmonary blood pressure. Clinical improvement
often is measured by a “6-minute walk test”—the distance that a patient can walk in 6 minutes. Stability and
improvement in this measurement correlate with better
survival. Levels of brain natriuetic peptide may be used
to follow the progress of patients with PH.14 A combination of echocardiography and biomarkers seems to offer
the best means to accurately screen for PAH.
Diagnosis of PAH requires the presence of PH with
2 other conditions. Pulmonary artery occlusion pressure
(PAOP or PCWP) must be less than 15 mm Hg (2,000
Pa), and PVR must be greater than 3 Wood units (240
dyn/sec/cm–5 or 2.4 mN/s/cm–5). Pulmonary hypertension is present when mean pulmonary artery pressure
(mPAP) exceeds 25 mm Hg (3,300 Pa) at rest or 30 mm
Hg (4,000 Pa) with exercise. Mean pulmonary artery
pressure should not be confused with systolic pulmonary
artery pressure (sPAP), which often appears on echocardiogram reports. A systolic pressure of 40 mm Hg typically implies an mPAP of more than 25 mm Hg.
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Figure.
Chest x-ray of a patient with ASD and
PH. The main pulmonary artery (long arrow)
and its main branches are enlarged, and the
peripheral pulmonary vessels by comparison are
“pruned.” The heart is enlarged and the shape
suggests right heart enlargement.
Reprinted with permission from Scognamilio G, et al. The essential role of imaging in the evaluation of patients with pulmonary
arterial hypertension in association with congenital heart disease.
Advances in Pulmonary Hypertension. 2012;11:171-182.
Physiologic Changes of Pregnancy
d.
Several cardiopulmonary physiologic changes with
pregnancy exacerbate PH. In the pulmonary system, minute ventilation increases by 50% at term. Arterial carbon dioxide decreases to about 34 mm Hg. Functional
residual capacity, expiratory reserve volume, and residual volume all decrease. Total lung capacity remains the
same because of an increase in chest circumference. The
smooth muscle relaxation effects of progesterone may
decrease airway resistance and improve function. Cardiac changes include a 50% increase in cardiac output,
with early increases in blood volume that increase stroke
volume. Afterload is reduced secondary to decreased
peripheral vascular resistance. Later, cardiac output is
augmented by tachycardia. Normally, PVR decreases
to allow these changes of pregnancy, an accommodation that is not possible in patients with PH. As afterload
increases from the higher PVR, the right ventricle cannot manage the increased cardiac output and begins to
fail. Sudden death from dysrhythmias may occur. Peak
plasma volumes develop at about 22 to 24 weeks of
pregnancy, and cardiac output peaks around 32 weeks.
At the time of delivery, pain stimulates the sympathetic nervous system with sudden significant increases
A N E ST H E S I O LO GY N E WS S P E C I A L E D I T I O N • O C TO B E R 2 0 1 3
79
Table 2. Prevalence of Pulmonary
Hypertension in Specific Subgroups
An observational study of 277 patients with HIV
infection found that 46% of patients had PH.9
A systematic review of several studies of patients
with obstructive sleep apnea estimated the prevalence of PH at 15% to 20%.10
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Studies of patients with chronic obstructive pulmonary disease estimated the prevalence of PH
at 10% to 30%.11
TREATMENT
AND
MANAGEMENT
Untreated PAH has 1-, 3-, and 5-year survival rates of
68%, 48%, and 34%, respectively. The addition of pregnancy worsens the prognosis significantly.21 As soon as
a diagnosis of PH is made, patients should be followed
with regular assessment of right ventricular (RV) function with TTE. If dysfunction is detected, early delivery
is recommended.3 Close follow-up using a multidisciplinary approach is essential, including obstetricians,
anesthesiologists, cardiologists, hematologists, and
neonatologists. Hospitalization by the second trimester is appropriate, given the high risk for hemodynamic
changes and preterm delivery.8 Monitoring is done by
echocardiography. Compression of the inferior vena
cava must be prevented. The patient’s paO2 should be
maintained above 70 mm Hg. Loop diuretics should be
used to treat right heart failure. Low-molecular-weight
heparin is indicated prior to delivery, and warfarin
should be used in the postpartum period.
Short of lung transplantation, no curative therapy
exists for PH. However, several treatments have shown
potential for improving outcome in patients with this
condition. Therapy is dictated in part by the cause,
whether arterial, venous, hypoxic, thromboembolic,
or other. Because PVH is synonymous with congestive heart failure, treatment attempts to optimize left
ventricular function by the use of diuretics, β-blockers,
angiotensin-converting enzyme (ACE) inhibitors, or
other agents, or to repair or replace the mitral or aortic
valves. Digoxin, diuretics, and oxygen have been advocated, but results are inconsistent unless for the specific
indication of preventing hypoxia.
High-dose calcium channel blockers (CCBs) are
useful in 5% of patients with idiopathic PAH who are
vasoreactive by pulmonary artery catheter measurements. Yet, these drugs have been prescribed to many
patients with non-vasoreactive PAH, leading to excessive morbidity and mortality. The criteria for vasoreactivity have changed: Only those patients whose mPAP
falls by more than 10 mm Hg to below 40 mm Hg with
an unchanged or increased cardiac output when challenged with adenosine, epoprostenol, or NO are considered vasoreactive.22 Of these, only half are responsive
to CCBs in the long term.23
Vasoconstriction results from the overexpression of
endothelial-1 and the reduction of NO and prostacyclin. Thus, therapy is targeted to these factors. Several
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The incidence of PH in patients with scleroderma is estimated at 6% to 60%, with the variance
based on the extent of disease.12
results of 26 pregnancies at 13 centers over a 3-year
period.19 Eight pregnancies ended in abortion; 3 women
died; and 1 required urgent heart–lung transplantation.
Among the 16 successful pregnancies, mothers who
survived had a lower PVR, 500 dyn/sec/cm5 versus
1,667 dyn/sec/cm5 for non-survivors. A retrospective
report, in the United States, of outcomes at 5 PH centers included 18 pregnancies over 2 years. Of those, 6
ended in abortion and 13 continued, all on sildenafil and
IV prostacyclins with cesarean delivery at 34 weeks.20
Three patients died, for a mortality rate of 16.7%.
In patients who took the diet medication fenfluramine/phentermine, there was a 23-fold increase in
the development of PH, often long after ingestion
of the drug combination.13
PH, pulmonary hypertension
in heart rate, blood pressure, and myocardial oxygen
consumption. Contractions during labor increase blood
volume by 300 to 500 mL and cause a 50% increase
in cardiac output. Cardiac output remains high for 48
hours or longer after delivery, and may require up to 6
months to return to prepregnancy levels.8 Maternal vagal
responses also may occur, leading to hypotension and
possibly sudden death.15 Valsalva maneuvers may further increase blood pressure and myocardial oxygen
consumption. Pregnancy is associated with a hypercoagulable state due to increased fibrin levels, reduced
fibrinolytic activity, and increased procoagulant activity
with higher resistance to activated protein C, lower protein S, and increased clotting factor activity (I, II, V,VII,
VIII, X, and XII).16 Any degree of thromboembolism contributes to a poor outcome in pregnant patients with PH.
Pulmonary Hypertension and Pregnancy
80
I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G
d.
Undiagnosed PH may manifest first with the stress of
pregnancy. Pulmonary hypertension also can develop
acutely during pregnancy. Sudden onset of dyspnea,
syncope, or chest pain should be investigated immediately. Differential diagnosis includes sleep apnea,
asthma, arteriovenous malformations, atrial myxoma,
amniotic fluid embolism, atrial septal defect, cardiomyopathy (dilated, hypertrophic, or restrictive), chronic
obstructive pulmonary disease, emphysema, mitral
regurgitation and stenosis, restrictive and interstitial
lung disease, and systemic lupus erythematosis.
Pulmonary hypertension affects a relatively small
number of pregnancies (approximately 0.0003%).17
Recent studies indicate a decline in mortality from
approximately 50% to 25%, with patients in the idiopathic PAH group showing the most improvement
(17%), perhaps the result of specific therapy that now
is more likely to be used in these patients.4,18 A multinational, prospective registry in Europe reported the
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agents have been introduced recently for primary and
secondary PAH. The clinical trials supporting the use of
these agents have been relatively small, and the only
measure consistently used to compare their effectiveness is the walk test. Many trials lack data on mortality,
clinical benefit, or time to progression.21,24
The most common cause of death in pregnant
patients with PH is RV failure. Treatment therefore has
aimed at reducing PVR. Three of the many vasoactive
pathways involved in the abnormal proliferation and
contraction of the smooth muscle cells of the pulmonary arteries have been targeted with drugs—endothelin receptor antagonists, phosphodiesterase type
5 (PDE5) inhibitors, and prostacyclin derivatives.24
The dual (ETA and ETB) endothelin receptor antagonist bosentan (Tracleer, T.A.P.) was approved in 2001.
Sitaxentan (Thelin, Pfizer), a selective endothelin receptor antagonist that blocks only the action of ETA, was
approved for use in Canada, Australia, and the European Union, but not by the FDA. In 2010, Pfizer withdrew the drug from the market because of its severe
side effects. Both agents, although effective, are teratogenic and should not be used if the pregnancy is to be
continued.8 A similar drug, ambrisentan (Letairis, Gilead
Sciences) is available in the United States.
Prostacyclin (prostaglandin I2) is commonly considered the most effective treatment for PAH.4,24 Epoprostenol (Flolan, GlaxoSmithKline) is given by continuous
infusion that requires a semipermanent central venous
catheter. This delivery system can cause sepsis and
thrombosis. Epoprostenol is unstable, and therefore
must be kept cold during administration. Because epoprostenol has a half-life of 3 to 5 minutes, the infusion
must be continuous and interruption can be fatal.
Other prostanoids have been developed. Treprostinil (Remodulin, United Therapeutics Corporation) can
be given intravenously or subcutaneously, but the subcutaneous injection can be painful and increases the
patient’s risk for sepsis. Studies establishing the effectiveness of the inhaled form of treprostinil (Tyvaso,
United Therapeutics Corporation) included mainly New
York Heart Association functional Class III patients,
those with symptoms and etiologies of idiopathic
or heritable PAH (56%), or PAH associated with connective tissue diseases (33%).25 Iloprost (Ilomedin,
Bayer Schering Pharma) also is used in Europe intravenously and has a longer half-life. Iloprost (Ventavis,
Bayer Schering Pharma AG/Actelion Pharmaceuticals)
was the only inhaled form of prostacyclin approved for
use in the United States and Europe, until the inhaled
form of treprostinil was approved by the FDA in July
2009. Administration by inhalation has the advantage
of selective deposition in the lungs with less systemic
side effects; however, cough and throat irritation commonly occur. Beraprost is an oral prostanoid available
in South Korea and Japan. A combination therapy is
usually advised.24 An investigational prostacyclin, selexipeg, is now in Phase II trials. A study of 43 patients
showed a 30% reduction in PVR.26
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Sildenafil (Revatio, Pfizer), a selective inhibitor of
cGMP-specific PDE5, was approved for the treatment
of PAH in 2005, and has been shown to be effective in a
selected subset of patients. In 2009, tadalafil (Adcirca,
Eli Lilly), another PDE5 inhibitor, also was approved.24
The NO signaling pathway is important for many
physiologic functions including vascular smooth muscle relaxation, neuronal signal transduction, and inhibition of platelet aggregation. The source of NO in vivo is
the enzyme NO synthase. The principal receptor for NO
is soluble guanylate cyclase (sGC), Several sGC activators are undergoing clinical trials.
Data on the fetal effects of these medications are
conflicting; however, anecdotal reports indicate safe
use for most of them.3 In contrast, a recent large study
of 30,000 women who had used selective serotonin
reuptake inhibitors late in pregnancy showed a 2-fold
risk for persistent PH in newborns.27
Numerous surgical procedures have been described
for the treatment of PH. Atrial septostomy creates a
communication between the right and left atria and
relieves pressure on the right side of the heart, but at
the cost of relative hypoxia. Lung transplantation cures
PAH but leaves the patient with the complications associated with transplantation, and a postsurgical median
survival of just over 5 years.28 Pulmonary thromboendarterectomy is a difficult, major procedure that currently is performed in a few centers but with apparent
good results in selected patients.
Anesthetic Considerations
d.
Even in the first 20 weeks of pregnancy, patients
with PAH may experience severe cardiorespiratory
problems. Successful management of these patients
depends especially on a team approach with obstetricians, cardiologists, cardiac surgeons, and anesthesiologists all in attendance and informed about
the patient’s history and clinical status. Starting with
preanesthetic care, hemodynamic status should be
assessed by clinical, radiological, and echocardiographic means. The goals of intraoperative management are to decrease the pulmonary blood flow and
PVR while maintaining cardiovascular and respiratory
stability. Invasive monitoring is recommended, even
with pulmonary artery catheterization and transesophageal echocardiography. Although percutaneous cardiopulmonary bypass often is not necessary, a setup
should be available in critical cases.
Although no anesthetic technique has proven superior, most patients are delivered under spinal or epidural
anesthesia.3 Propofol has been shown to decrease leftto-right flow and increase right-to-left flow, thus reducing the pulmonary-to-systemic flow ratio.29 Inhaled
iloprost (prostaglandin) has been shown to decrease
both pulmonary artery pressure and PVR in most
patients.29 One report has been published of successful
delivery at 30 weeks by cesarean under epidural anesthesia with central monitoring and a continuous infusion of prostaglandin E1.30 Another case using the same
A N E ST H E S I O LO GY N E WS S P E C I A L E D I T I O N • O C TO B E R 2 0 1 3
81
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anesthetic technique ended in sudden collapse after
delivery and death of the patient about 16 hours later.31
Because ACEs are present in high concentrations in
lung tissue with increased susceptibility for PAH, use of
ACE inhibitors, such as enalapril or captopril, may prove
beneficial.29
Factors as hypoxia, airway obstruction, and hypoventilation can induce failure.
Of note, hypotension may develop during delivery
from the several medications used to treat PH, including oxytocin, pulmonary vasodilator drugs, inotropes
(dobutamine), and analgesics, as well as blood loss.
Vasopressin preferentially increases systemic vascular resistance without increasing PVR, and is a viable
option to support blood pressure without compromising RV function. Maternal death is most likely to occur
in the postpartum period when maximum fluid shifts
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Conclusion
Mortality from PAH during pregnancy has decreased
in recent years, but remains high well into the postpartum period. In patients who become pregnant either
with preexisting PAH or who develop the condition
during pregnancy, abortion is still the recommended
course of action. For patients who do not elect to terminate their pregnancy, second-trimester admission to
the hospital is warranted, with early operative delivery.
Several drugs are approved or are currently undergoing trials to attempt to decrease pulmonary pressures.
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