SE M I N A R S I N P E R I N A T O L O G Y ] (2014) ]]]–]]]

Available online at www.sciencedirect.com

www.elsevier.com/locate/semperi

Pulmonary arterial hypertension in pregnancy

Sarah G. Običan, MDn, and Kirsten L. Cleary, MD
Division of Maternal–Fetal Medicine, Department of Obstetrics and Gynecology, Columbia University College
of Physicians and Surgeons, 622 W 168th St, PH 16-66, New York, NY 10032

article info abstra ct

Keywords: Pulmonary hypertension is a medical condition characterized by elevated pulmonary

pulmonary hypertension arterial pressure and secondary right heart failure. Pulmonary arterial hypertension is a
pregnancy subset of pulmonary hypertension, which is characterized by an underlying disorder of the
Eisenmenger’s syndrome pulmonary arterial vasculature. Pulmonary hypertension can also occur secondarily to
pulmonary arterial hypertension in structural cardiac disease, autoimmune disorders, and toxic exposures. Although pregnan-
pregnancy cies affected by pulmonary hypertension and pulmonary arterial hypertension are rare, the
pathophysiology exacerbated by pregnancy confers both high maternal and fetal mortality
and morbidity. In light of new treatment modalities and the use of a multidisciplinary
approach to care, maternal outcomes may be improving.
& 2014 Elsevier Inc. All rights reserved.

Introduction secondary disorders that have a similar clinical course, such

Pulmonary hypertension (PH) is a medical condition charac-
terized by elevated pulmonary arterial pressure and secon-
dary right heart failure. PH commonly occurs secondarily to
an underlying medical condition such as heart or lung
disease. More rarely, PH can occur as a primary condition
and is included in a group of disorders termed pulmonary
arterial hypertension (PAH). As the name suggests, PAH is
directly caused by an underlying disorder of the pulmonary
arterial vasculature. A narrowing of the pulmonary arterial
bed occurs due to the “imbalance” of vasoactive mediators
such as endothelin-1, prostacyclin, and nitric oxide.1 A mean
pulmonary artery pressure greater than or equal to 25 mmHg
at rest defines PH.
PH has recently been reclassified into subgroups by the
World Health Organization based on underlying etiology,
natural history, and response to treatment2 (Table). Group 1
is more specifically termed pulmonary arterial hypertension
(PAH). This group includes what was known previously as
primary PH or idiopathic PH but now also includes related
as drug-related or those secondary to a connective tissue
disease. Although rare, primary or idiopathic PH is a rapidly
progressing disease. Mean survival is between 2.8 and 5 years,
especially in younger patients.3–5 PH associated with con-
nective tissue diseases such as lupus or scleroderma also
carries a very poor prognosis.6 Group 1 also includes those
patients with congenital heart disease such as a ventricular
septal defect (most common), atrial septal defect, or a patent
ductus arteriosus. These cardiac defects cause left-to-right
shunting of blood flow, leading to chronic overperfusion of
the pulmonary vasculature and increased pulmonary arterial
pressures. Over time, right heart hypertrophy occurs, even-
tually leading to reversal of shunting. The right-to-left shunt-
ing of deoxygenated blood leads to systemic hypoxemia. This
pathophysiology is known as Eisenmenger's syndrome.
PH is a progressive condition that results in right ventric-
ular strain and eventual right heart failure. Increased pulmo-
nary vascular resistance (PVR) and pressure causes an
increase in right ventricular afterload. With acute changes
of the PVR, the thin-walled right ventricle is challenged to

n
Corresponding author.
E-mail address: sgo2105@columbia.edu (S.G. Običan).

http://dx.doi.org/10.1053/j.semperi.2014.04.018
0146-0005/& 2014 Elsevier Inc. All rights reserved.
2 SE M I N A R S I N
Table – Pulmonary hypertension classification.
Group 1 Pulmonary arterial hypertension
a. Idiopathic pulmonary arterial hypertension
b. Associated with other diseases (such as systemic
sclerosis, HIV, schistosomiasis, and portal
hypertension) or congenital heart disease
c. Drug/toxin induced
Group 2 Pulmonary hypertension due to left heart disease
a. Systolic or diastolic dysfunction
b. Valvular disease
Group 3 Pulmonary hypertension due to lung disease,
hypoxia, or both
a. COPD
b. Sleep apnea
c. Interstitial lung disease
d. Chronic exposures to high altitude
Group 4 Chronic thromboembolic pulmonary hypertension
Group 5 Unclear/multifactorial mechanism
accommodate the increased cardiac output, and this leads to
acute right heart failure. In chronic PH, the right ventricle
hypertrophies lead to increased oxygen consumption, poor
contractility, and again eventual failure. The right ventricular
malfunction also affects the left ventricular filling, causing a
decreased cardiac output and oxygen delivery.7
Pregnancies affected by PH are rare with an incidence of
1.1/100,000 women.8 Recently, pregnancies affected by PH
have seen an improvement in survival due to newer treat-
ment modalities and the utilization of a multidisciplinary
approach to treatment. Despite these improvements, the
consequences of PH are exacerbated by the physiologic
changes of pregnancy, which contribute to a high maternal
mortality reaching 30–56%.9 Unfortunately, fetal risks are also
high with an increased risk of growth restriction, increased
risk of preterm delivery, and increased perinatal mortality.10
Given the poor maternal and fetal outcomes, women with a
diagnosis of PH are encouraged to use highly effective contra-
ceptive methods and in the case of a pregnancy to strongly
consider an early termination. Women who choose to con-
tinue a pregnancy in this high-risk setting should be cared for
in a tertiary care center under the supervision of a multi-
disciplinary team with strong critical care team support.
Physiologic changes of pregnancy and effects of
pulmonary arterial hypertension
Every organ system is affected by the physiologic changes of
pregnancy. The cardiovascular system is especially burdened
by an increase in blood volume up to 50%, peaking at 32
weeks of gestation with 4700–5200 ml.3 Both heart rate and
stroke volume are increased in pregnancy, resulting in an
increased cardiac output by 30–50% by the early third trimes-
ter.3 To compensate for this increased blood flow require-
ment, progesterone and other mediators with vasodilatory
properties cause a decrease in both pulmonary vascular
resistance and systemic vascular resistance. Unfortunately,
in women with existing pulmonary arterial hypertension, the
P E R I N A T O L O G Y ] (2014) ]]]–]]]
underlying pulmonary vascular disease hinders the normal
pulmonary vasodilatary mechanisms in pregnancy. There are
abnormal responses to vasoactive substances including pro-
gesterone. This leads to a paradoxical increase in pulmonary
arterial pressures in these women as cardiac output
increases. This dangerous combination of increased cardiac
output demand and increased pulmonary vascular resistance
leads to right heart failure. Furthermore, progesterone effects
also increase the tidal volume, causing a mild respiratory
alkalosis and a decreased functional residual capacity.7 Most
morbidity and mortality from PH occurs in the second and
early in the third trimester and immediately postpartum,
when hemodynamic changes are at the greatest.
Peripartum and postpartum changes
Labor may involve fluid shifts that increase the cardiac
output, causing increased strain on the right heart and the
pulmonary vascular bed.11 This poses a problem to women
who have difficulty in increasing their cardiac output. Similar
to during pregnancy, the postpartum period is also compli-
cated by significant hemodynamic changes. Both cardiac
output and stroke volume increase after delivery while the
heart rate decreases by 15%.12 After delivery the uteropla-
cental blood flow shifts into the intravascular space, which is
largely responsible for the resultant increase in both cardiac
output and stroke volume. The relief of uterine compression
on the vena cava increases the cardiac preload as well.
Additionally, hemodynamic alterations occur with blood loss,
approximately 500 ml in a vaginal delivery and 1000 ml in a
cesarean delivery, which causes a decrease in preload. Lastly,
there is a quick increase in the systemic and pulmonary
vascular resistance immediately after delivery. These hemo-
dynamic changes are only a few that make postpartum
management difficult in patients with PH.7
Clinical presentation
Unfortunately, normal pregnancy-related symptoms may
mask the presenting symptoms of PH. Notably, fatigue and
shortness of breath are the most common symptoms. Chest
pain from myocardial ischemia may be present.13 Right-sided
heart failure may cause increased dizziness, syncope, and
edema of the lower extremities.13
Management in pregnancy
Thromboembolic/hypercoagulable state
Pregnancy is a hypercoagulable state due to a multitude of
factors. Physically, the enlarged uterus causes increasing
compression of the iliac veins and the vena cava, leading to
venous stasis. Hormonal changes such as increased proges-
terone also increase venous stasis via their vasodilatory
effects. Additionally, there are hematologic changes that
exacerbate the hypercoagulable state, such as an increase
in clotting factors, a resistance to activated protein C, and a
decrease in protein S.14 Also, fibrin is decreased in the setting
 SEM I N A R S I N P E R I N A T O L O G Y
of decreased fibrinolytic activity.7 Overall, the risk of throm-
boembolic events is approximately 5-fold higher in the
pregnant than in the nonpregnant state.14
Use of thromboprophylaxis in pregnancies affected by PH is
not well defined. However, given the heightened consequen-
ces of a thrombotic event in this population, most clinicians
place their patients on a prophylactic anticoagulation regimen
during pregnancy and postpartum. The two frequently utilized
anticoagulants in pregnancy include heparin and low-
molecular-weight heparin. Both have large molecular weights
that do not allow them to cross the placenta and thus cannot
be a potential teratogen or cause fetal hemorrhage.15 Con-
versely, Coumadin (warfarin) does cross the placenta and can
cause a Coumadin embryopathy consisting of nasal hypopla-
sia and stippled epiphyses.16 Women with Eisenmenger's
syndrome and a patent foramen ovale have a higher risk of
paradoxical emboli and so perhaps should be even more
strongly considered for prophylactic anticoagulation. Some
authors comment on the cessation of anticoagulation at
around the time of delivery to minimize blood loss.10,17 Clinical
presentation of the individual patient should be taken into
consideration such that those patients with a history of a
previous blood clot should be on full doses of anticoagulation
while those with a bleeding diathesis may require a lower
prophylactic dose or cessation of anticoagulation altogether.
Additionally, the use of extracorporeal membrane oxygenation
(ECMO) necessitates a unique anticoagulation formulation and
again should be tailored to the patient specifically.
Medications for pulmonary arterial hypertension
Often there is limited data associated with the use of
medications to treat PH in pregnancy. Some of these medi-
cations may be in the absence of viable alternatives or when
benefits outweigh the risk. This is often the case when
dealing with a pregnant patient with PH and often after
appropriate counseling, the fetal risks may need to be
assumed for the benefit of the mother.
Prostacyclin analogs
Epoprostenol is a synthetic prostacyclin analog IV medication
approved for the treatment of pulmonary arterial hyperten-
sion. It works as a vasodilator of both systemic and vascular
beds and also inhibits platelet clumping. Its advantages include
a rapid dose titration and a short half–life.18 A disadvantage is
that it may cause thrombocytopenia and may require platelet
transfusions.11 There have been many reports of the successful
use of prostacyclin analogs during pregnancy.19–21 As of yet
there are no well-controlled studies to evaluate the teratogenic
effects of infused epoprostenol in pregnant women. According
to product labeling, use of epoprostenol in animal studies,
using higher doses than normally used in humans, did not
reveal an increased risk of birth defects or miscarriage rate.
Inhaled nitric oxide
As a pulmonary vasodilator, it has been successfully used in
critically ill patients with pulmonary arterial hypertension.22
] (2014) ]]]–]]] 3
It has also been used successfully in pregnant patients.9,23
Unfortunately, long-term use is associated with rebound PH
after withdrawal and met-hemoglobinemia.24
Iloprost
Iloprost is a synthetic eicosanoid with molecular action
similar to those of prostacyclin. Iloprost is a vasodilator as
well as an inhibitor of platelet aggregation. Administration of
iloprost in rabbits (doses 40 mg/kg/d) and monkeys (up to
0.04 mg/kg/d IV) did not increase the incidence of congenital
anomalies (reprotox/product label). However, in rats, doses of
0.01 mg/kg/d or above increased the risk of shortened digits in
the pups.25 It is hypothesized that this teratogenic effect may
be in part due to hypoperfusion associated with the iloprost's
vasodilatative effects. There are successful human reports of
iloprost use with some pregnancies exposed early in the first
or second trimester.26,27 There were no teratogenic outcomes
in the case reports attributed due to the use of iloprost.
Bosentan
Endothelin-1 is a vasoconstrictor that is overexpressed in
lung tissue of PH patients. As endothelin-1 has a pathogenic
role in pulmonary arterial hypertension, blockade of endo-
thelin receptors has been used in the treatment of PAH.28
Bosentan (Tracleer) is contraindicated in pregnancy as it has
been shown to be teratogenic in mice. At doses twice that
recommended for human use, there were malformations of
the head, eyes, face, and large blood vessels.29 Additionally,
bosentan prevents the constriction of the fetal ductus arterio-
sus.30,31 Whenever possible, the use of bosentan should be
avoided in pregnancy. Furthermore, it should not be used in
women relying on a hormonal contraceptive. Some patients
on this medication may have a large decrease in serum
progestin concentrations (manufacturer's recommendation).
PDE-5 inhibitors (Sildenafil and Tadalafil)
Phosphodiesterase-5 inhibitors, such as Sildenafil, cause non-
specific vasodilatation of the pulmonary and systemic vas-
cular beds. They also have an inotropic effect on the
hypertrophic right ventricle.7 There have been reports of its
successful use in pregnancy.19,32,33
Maternal monitoring
Frequent office visits are recommended to allow for close
monitoring of patients. In the first trimester, a thorough
evaluation of medication use should be done to balance the
dual goals of decreasing teratogenic effect and maximizing
maternal PAH therapy. There should be a consideration of
anticoagulation. In coordination with a multidisciplinary
team, monthly echocardiograms may be offered. Addition-
ally, frequent B-type natriuretic peptide (BNP) testing may be
indicated. Maternal worsening usually occurs in the second
and early third trimester.17 Patients with worsening symp-
toms in early pregnancy should be strongly urged for a
termination as it predisposes to a worse outcome.17 In those
4 SE M I N A R S I N
patients who deteriorate in the late second and third trimes-
ter (or for those patients who decline termination) hospital-
ization should be considered.
Fetal monitoring
Fetuses of mothers affected by PH are at an increased risk of
poor outcome such as an intrauterine fetal demise, neonatal
death, and preterm delivery. Preterm delivery is a significant
problem, in some series occurring in up to 100% of affected
pregnancies.10,34 Iatrogenic deliveries are increased due to
worsening maternal condition, or in those patients with
Eisenmenger's due to PDA pathophysiology, which resulted
in decreased oxygenation of the maternal lower extremities
as well the uterus. This may have contributed to poor fetal
growth, and often fetuses require an early delivery for
worsening fetal status. We recommend monthly ultrasounds
to assess fetal weight. Increased fetal surveillance may be
needed depending on the individual patient's case.
Delivery
The peripartum period is particularly complicated due to the
vasovagal reactions to pain and anesthesia, volume shifts of
blood loss, autotransfusion due to uterine contractions,
increased acidosis, and hypercarbia. All of these factors
contribute to further pulmonary vascular resistance and
acute risk of thromboembolic events.13
The preferred mode of delivery continues to be a topic of
debate. Long-term teaching has often preferred a vaginal
delivery for these high-risk patients in order to minimize
the extensive fluid shifts associated with a cesarean delivery.
Delivery is usually accomplished in the left lateral position in
order to decrease the pressure on the patient's vena cava. Use
of the Valsalva maneuver can decrease venous return and
affect the preload for these patients. An abrupt change in
preload in patients affected by PH can cause a drop in cardiac
output and cardiopulmonary collapse.11 To decrease the
second stage of labor, use of forceps or vacuum may be
utilized. Pain response during childbirth can increase in the
sympathetic nervous system and an increase in the heart
rate. This too may lead to cardiopulmonary collapse, and
thus early timing of appropriate pain control is warranted.
Many women will likely have to deliver preterm due to
increasing maternal or fetal complications. An induction of
labor may prove to be difficult with an unfavorable cervix.
In some studies and hospital centers, cesarean delivery is
the mode of delivery of choice. It provides ample time for the
surgical and the medical team preparation, including prepa-
ration for ECMO if needed. Additionally, a cesarean section
decreases the risk of hemodynamic risks of the Valsalva
maneuver during the second stage of labor as well as
autotransfusion associated with uterine contractions. Cesar-
ean section, however, may be associated with increased fluid
shifts and further exacerbate the PH pathophysiology. In
support of cesarean delivery, the article by Wang et al.
describes 13 cases of pregnant women diagnosed with Eisen-
menger's syndrome. Most women acquired this pathology
P E R I N A T O L O G Y ] (2014) ]]]–]]]
due to an uncorrected VSD. All women were monitored in the
hospital and received O2 and vasodilatory therapy.35 Cesar-
ean section was performed in all patients, and 12 of 13
patients successfully delivered without peripartum maternal
mortality.
Management of blood loss is tenuous during a delivery of a
patient with PH. In a review of 12 pregnancies (9 women) with
PH, the mean blood loss was 711 ml (range: 300–1000 ml).
Blood loss was greater than 500 ml in six out of nine cases.36
Medications used to treat blood loss may have adverse effects.
For example, methergine causes vasoconstriction and hyper-
tension.36 Oxytocin causes an increase in pulmonary vascular
resistance and tachycardia.37 The two women in the above
series received boluses of Pitocin with one of these deaths
potentially associated with Pitocin administration.
Anesthetic concerns
The goal of anesthesia in patients with PH is to avoid an
increase in peripheral vascular resistance, pulmonary arterial
pressure, avoiding changes in preload, maintaining left ven-
tricular afterload, and RV contractility.38,39 Therefore, steps
should be taken to avoid pain, acidosis, and hypoxemia.
Whenever possible, use of a specialized obstetric anesthesia
team should be utilized. Inotropes, pressors, and afterload
reducers should all be readily available in the delivery/
operating room.38
Regional anesthesia
Regional anesthesia offers excellent pain control and allows
the patient not to be intubated. However, its drawback
include that in large doses, it may cause a sympathetic block,
decreasing venous return to the heart.17 Additionally, spinal
anesthesia may lead to hypotension and a decrease in pre-
load, making a patient hemodynamically unstable. It can also
produce rebound worsening of PH and thus should be
avoided in patients with PH.17
Traditionally, the preferred anesthetic approach to manage-
ment has been a slow-dosed epidural. More recently, several
authorities suggest a combined spinal and epidural anesthetic
approach to be preferred as it offers excellent pain control as
well as decreased risk of nausea and hypotension.17,40
General anesthesia
There are significant concerns with general anesthesia in
patients with PH. It may decrease cardiac contractility but
increase pulmonary vascular resistance and pulmonary arte-
rial pressures.41 Positive pressure ventilation may also
decrease the venous return, further exacerbating the PH
pathophysiology. Also, the use of general anesthesia, specif-
ically volatile agents, increases the risk of uterine atony.
Contraception
Preconception counseling is of utmost importance with
patients affected by PH. Women of reproductive age should
 SEM I N A R S I N P E R I N A T O L O G Y
have appropriate gynecologic care with strong attention to
contraception. Specific maternal morbidity and mortality
rates can be approximated given the etiology, and risks for
poor fetal outcomes should also be discussed with the
patient. Given risks of a pregnancy in the setting of maternal
PH, two contraceptive methods should be used. Long-term
effective contraceptive methods such as an intrauterine
device or in-office Essure placement are possible options.
If pregnancy occurs, termination should be offered and
encouraged as early as possible in pregnancy before the full
effect of pregnancy-related physiologic changes occurs. Cer-
tain drugs used in the treatment of PH may have teratogenic
effects on the fetus. Bosentan (Tracleer) is an endothelin
receptor antagonist, which according to product labeling is
contraindicated in pregnancy. As mentioned above, this is
based on animal data, namely pregnant rats that had
increase in malformations of the head, eyes, face, and large
blood vessels at twice the dose recommended for human
use.29 Additionally, Bosentan may cause a drug interaction
with the use of hormonal contraceptives, necessitating the
use of a second form of birth control.11
If despite counseling, a patient chooses not terminate a
pregnancy, certain medication, despite being teratogenic,
may be still be offered in order to maximize maternal out-
come. Often patients are well controlled on a certain medi-
cation, and its teratogenic effects should be weighed against
poor maternal health and poor fetal outcomes associated
with maternal hypoxia. This should be an important aspect of
extensive patient counseling.
ECMO
Extracorporeal membrane oxygenation (ECMO) is a form of
extracorporeal gas exchange, which uses an artificial mem-
brane in order to support the lung functions while the native
lung recovers from a physiological insult. In this mechanism,
a large-bore catheter is placed in a major vein, and deoxy-
genated blood is removed from the patient's body. This blood
is then pumped through an oxygen membrane, and oxy-
genated blood is returned into a vein or artery through
another catheter. ECMO has been used in the treatment of
neonatal pulmonary complications and has increasingly been
used for treatment of pregnant patients with severe acute
respiratory insufficiency or postpartum hemorrhage.42–45 Its
efficacy and safety is unfortunately not well delineated in
pregnancy.
Anticoagulation is needed to allow the use of ECMO treat-
ment, and as such, bleeding complications of up to 54% have
been noted in both the pregnant and the nonpregnant
population.46 While there is limited case report evidence that
ECMO is beneficial in pregnancy, it is thought that maternal
stabilization may help stabilize a concerning fetal status.
Conclusion
Despite better understanding of pulmonary hypertensive
pathophysiology and improvements in treatment modalities,
pregnancy in the setting of PAH is associated with a high
] (2014) ]]]–]]] 5
maternal and fetal morbidity and mortality. Preconception
counseling should be provided. An effective form or birth
control should be provided. Given a grave prognosis, should a
patient become pregnant, a termination in early pregnancy
should be recommended. Terminations in these high-risk
pregnancies should be offered in the hospital setting. If a
patient insists on continuing a pregnancy, she should be
informed of the extensive risks to her as well as her fetus.
A multidisciplinary team should be used to manage such
complicated pregnancies. We recommend frequent office
visits throughout the duration of the pregnancy in order to
identify potential worsening symptoms early. Admission to
the hospital may provide better ability of a multidisciplinary
approach, especially in a patient with those worsening
symptoms. Where available, an ECMO team should be con-
sulted and the technology utilized in the direst cases.
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