Pulmonary Hypertension in Children - Classification, Evaluation, and Diagnosis - UpToDate

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Pulmonary hypertension in children: Classification,

evaluation, and diagnosis
AUTHOR: Mary P Mullen, MD, PhD
SECTION EDITORS: David R Fulton, MD, George B Mallory, MD
DEPUTY EDITOR: Carrie Armsby, MD, MPH
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jan 2024.

This topic last updated: Apr 04, 2023.
INTRODUCTION
Pulmonary hypertension (PH) is a disease characterized by elevated pulmonary artery

pressure (PAP), which can result in right ventricular (RV) failure. In children, PH is most
commonly associated with underlying cardiac or lung disease (eg, bronchopulmonary
dysplasia). PH may also be idiopathic or familial. Other causes of PH are rare in childhood
( table 1). PH can be associated with considerable risk of morbidity and mortality.
Management of children with PH requires a multidisciplinary team with experience and
expertise in this area.
The classification, evaluation, and diagnosis of PH in children are reviewed here.

Management and prognosis of PH in children is reviewed separately. (See "Pulmonary
hypertension in children: Management and prognosis".)
Persistent PH of the newborn, PH associated with bronchopulmonary dysplasia, the

pathogenesis of PH, PH in adults (including adults with congenital heart disease), and
Eisenmenger syndrome are reviewed in greater detail separately:
● (See "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and
diagnosis".)
● (See "Pulmonary hypertension associated with bronchopulmonary dysplasia".)
● (See "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group
1)".)
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● (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in

adults" and "Treatment of pulmonary arterial hypertension (group 1) in adults:
Pulmonary hypertension-specific therapy" and "Treatment and prognosis of pulmonary
arterial hypertension in adults (group 1)".)
● (See "Pulmonary hypertension with congenital heart disease: Clinical manifestations
and diagnosis".)
● (See "Pulmonary hypertension with congenital heart disease: Clinical manifestations
and diagnosis" and "Pulmonary hypertension in adults with congenital heart disease:
General management and prognosis".)
REFERRAL
The diagnostic evaluation of PH in pediatric patients should be carried out by or in close

collaboration with practitioners with considerable experience and expertise in this area. Early
referral is critical since treatment for many types of PH is less effective if provided at a late
stage of the disease.
TERMINOLOGY
The following terms are used throughout this topic:
● Pulmonary hypertension (PH) – PH refers to elevated pulmonary artery pressure (PAP;

mean PAP >20 mmHg). PH can be due to a primary elevation of pressure in the
pulmonary arterial system alone, increased blood flow through the pulmonary
circulation (eg, systemic-to-pulmonary shunting lesions), or elevation of pressure in the
pulmonary veins.
● Transpulmonary gradient (TPG) – TPG is the pressure gradient across the pulmonary
circulation. It is the difference between the mean PAP and the left atrial pressure (LAp).
● Pulmonary vascular resistance (PVR) – PVR is a measurement of the resistance in the

pulmonary circulation. It provides an estimation of whether the cross-sectional area of
the pulmonary vascular bed is reduced (elevated PVR indicates reduced cross-section
area). PVR is the ratio of the TPG to pulmonary blood flow (Qp): PVR = TPG/Qp
(calculator 1). Normal PVR is ≤1.5 Wood units, with Qp indexed to body surface area;
mean PAP of 20 mmHg corresponds to PVR of approximately 3 to 4 Wood units,
depending on Qp and LAp.
● Pulmonary arterial hypertension (PAH) – PAH refers to elevation of the pressure in

the pulmonary arterial system (PAP >20 mmHg) and elevated PVR (PVR >3 Wood units)
with normal pulmonary venous pressure (pulmonary artery wedge pressure <15
mmHg). PH occurring in the context of certain underlying diseases (eg, lung disease) is
not classified as PAH. (See 'Classification' below.)
● Pulmonary venous hypertension – Pulmonary venous hypertension refers to

elevations of pressure in the pulmonary venous and pulmonary capillary systems
(pulmonary artery wedge pressure ≥15 mmHg).
● Pulmonary hypertensive vascular disease (PHVD) – PHVD (previously called

pulmonary vascular obstructive disease) refers to pathologic remodeling of pulmonary
small vessels that results in narrowing the vascular lumen and loss of small pulmonary
vessels. PHVD is characterized by elevated PVR and/or TPG; PAP is typically elevated but
may be <20 mmHg in some cases (eg, single ventricle with cavopulmonary palliation).
Although there are important distinctions between the terms PH and PAH (as noted above),
for simplicity, the term PH will be generally used in this topic review, except when the
distinction is important.
DEFINITION
For children and infants >3 months old, the definition of PH is the same as in adults: mean
pulmonary artery pressure (PAP) >20 mmHg at sea level [1-3]. This definition is based on the
2018 6th World Symposium on Pulmonary Hypertension (WSPH) [1]. Earlier guidelines used a
slightly higher cutoff of ≥25 mmHg [2,3]. However, the pressure cutoff for assigning the
diagnosis of PH is somewhat arbitrary and the concept of PH as being a disease (implying
the need for therapy) is useful only when it acquires nuance.
In addition to the PAP value, the following questions should be addressed:
● Is the patient old enough that the elevated PAP is not simply a slower-than-normal
decline in fetal pulmonary vascular resistance (PVR)?
● Does the elevation in PAP reflect an abnormal pulmonary vascular bed or is it

secondary to increased flow or pulmonary venous pressure?
● To what degree does the PH impact right ventricle (RV) function?
● Is the patient disproportionately affected by a small increase in PAP (eg, patients with
Fontan circulation)?
The following sections discuss these issues in greater detail:
● Neonates – PVR is high in utero and falls rapidly after birth. PAP normally reaches adult
levels during the first few weeks of life. However, even if the PAP has fallen at the usual

rate, the neonatal lung reacts to vasoconstrictive stimuli (eg, alveolar hypoxia) much
more vigorously than does the mature lung, so stressors provoke a greater response
than later in life. In addition, occasionally the neonatal transition to a low-resistance
pulmonary circulation is delayed, and despite otherwise healthy lungs, the mean PAP
remains elevated at ≥20 mmHg (sometimes even suprasystemic). These asymptomatic
neonates require close follow-up; however, in most cases, the PH resolves over the first
one to three months and they are generally not considered to have pathologic PH
despite elevated PAP levels.
● Cardiac shunting lesions or left heart disease – Patients with systemic-to-pulmonary

cardiac shunting lesions may have PH due to increased pulmonary blood flow (Qp)
rather than pulmonary vascular disease, per se. Similarly, left heart disease that is
associated with elevated left atrial pressure (Lap; eg, left ventricular failure,
cardiomyopathy, mitral or aortic valve stenosis or other left ventricular obstructive
lesions) may cause PH due to pressure "back-up" (ie, pulmonary venous hypertension).
Patients in these categories may actually have healthy pulmonary vessels or reversible
pulmonary vascular abnormalities. Defining PH solely on the basis of only the PAP fails
to take into account the amount of Qp or pulmonary venous pressure as a determinant
of PAP. By contrast, the PVR takes these variables into consideration (PVR = [mean PAP –
mean LAp]/Qp). (See 'Terminology' above.)
● RV function – The RV is the primary end organ of interest in PH. Elevated PAP is mostly
relevant insofar as it impacts RV systolic and diastolic function (ie, its capacity to
generate blood flow) at rest and with exercise. A mean PAP considerably exceeding 20
mmHg may be well tolerated in a patient whose RV is well adapted to high pressure.
Conversely, a seemingly minor increase in PVR may have critical impact on RV function
in certain patients, even with mean PAP levels that are <20 mmHg. For patients with
single-ventricle physiology (eg, hypoplastic left heart syndrome) and cavopulmonary
palliation (eg, Fontan palliation), there is no pump to drive blood across the pulmonary
circulation and a relatively minor increase in PVR can severely compromise cardiac
output. (See "Management of complications in patients with Fontan circulation".)
● Conditions at time of measurement – Measurements of PAP in the echocardiography

or cardiac catheterization laboratory may not reflect the PAP at other times and under
different conditions. For example, patients with bronchopulmonary dysplasia may have
little elevation of PAP when healthy but a marked and clinically important increase in
the setting of viral respiratory infection. In addition, patients with PH have relatively
noncompliant pulmonary vascular beds, so a modestly elevated PAP at rest (with no
appreciable impact on the patient's resting physiology) can increase substantially with
exercise.

PHYSIOLOGY AND PATHOGENESIS
Increased pulmonary artery pressure (PAP) is caused by one or more of the following:
● Decreased cross-sectional area of the pulmonary vascular bed

● Increased pulmonary blood flow (Qp)
● Increased pulmonary venous pressure (most commonly due to elevated left atrial
pressure [LAp])
As previously noted, pulmonary vascular resistance (PVR) provides an estimation of whether

the cross-sectional area of the pulmonary vascular bed is reduced (elevated PVR indicates
reduced cross-section area). Reduced cross-sectional area is due to reduced luminal
diameter of small pulmonary vessels and/or a decreased number of these vessels. In most
types of PH, small pulmonary arteries are most affected, although small or large pulmonary
veins may be the primary site of obstruction in some forms of PH [4-7]. Peripheral
pulmonary artery stenosis involves larger pulmonary arteries and can also cause PH [8]. (See
"Pulmonic stenosis in infants and children: Clinical manifestations and diagnosis".)
The caliber of a small pulmonary arteries or pulmonary veins may be narrowed by active
vasoconstriction and/or anatomic changes; often, both are present.
● Vasoconstriction – Many patients with PH (eg, those with idiopathic PH, chronic lung
disease, or structural congenital heart defects) have some degree of active
vasoconstriction, as revealed by a fall in PAP with administration of a vasodilator (eg,
inhaled nitric oxide) [9].
● Anatomic changes – Pulmonary hypertensive vascular disease (PHVD; previously

referred to as pulmonary vascular obstructive disease) refers to pathologic remodeling
of small vessels and narrowing of the vascular lumen through medial hypertrophy,
proliferation of "neointimal cells" (whose origin is unclear [10]), and deposition of
connective tissue in pulmonary arteries. The number of small pulmonary arteries may
also be reduced by virtue of complete occlusion of the lumen by neointimal cells or by
in situ thrombi [4]. A paucity of small pulmonary arteries can also result from the failure
of such vessels to develop (eg, with bronchopulmonary dysplasia, congenital
diaphragmatic hernia, or, possibly, high pressure/high flow cardiac defects) [11]. Medial
hypertrophy can resolve when the inciting stimulus is removed (eg, repair of a large
ventricular septal defect in the first year of life). In infants with bronchopulmonary
dysplasia or congenital diaphragmatic hernia, pulmonary hypertensive vascular disease
usually gradually improves with growth of new pulmonary arterioles as a part of normal
lung growth during the first few years of life. By contrast, pulmonary hypertensive

vascular disease due to intimal proliferation and connective tissue deposition has much
less potential to resolve with therapy.
A comprehensive mechanistic understanding of why and how disease occurs in pulmonary

blood vessels is lacking, but a considerable amount of knowledge about the pathogenesis
has been gained through translational and laboratory investigations. Factors that may
contribute to the development of PHVD include:
● Developmental abnormalities – Abnormal pulmonary vascular development,

occurring pre- and/or postnatally, can cause increased PVR. Causes include
bronchopulmonary dysplasia, congenital diaphragmatic hernia, and Down syndrome
[1,12,13]. Some of the genetic variants discussed below (eg, TBX4 gene mutations) can
also cause abnormal pulmonary vascular development.
● External stimuli – Multiple agents and insults external to the lung itself can provoke
pulmonary vasoconstriction and pathologic vascular remodeling. Examples include:
• Alveolar hypoxia – Examples of extrinsic causes of alveolar hypoxia include living at

a high altitude, intrinsic lung disease (without supplemental oxygen), and sleep-
disordered breathing [14-16]. (See "Management of obstructive sleep apnea in
children", section on 'Consequences of untreated obstructive sleep apnea' and
"High-altitude disease: Unique pediatric considerations", section on 'High-altitude
pulmonary hypertension'.)
• Increased mechanical forces – Congenital intracardiac shunting lesions and/or left

heart disease may produce increased hydrodynamic forces that can provoke PHVD.
These include (listed roughly in order of potency) lesions associated with increased
Qp and elevated PAP (eg, large ventricular septal defect), lesions with elevated PAP
and normal Qp (eg, mitral stenosis), and lesions with increased Qp in isolation (eg,
atrial septal defect) [17]. (See "Pathophysiology of left-to-right shunts", section on
'Pulmonary hypertension'.)
• Toxins, drugs, and infectious agents – Examples include contaminated rapeseed oil,
fenfluramine derivatives [18], methamphetamines, HIV, and schistosomiasis [19].
(See "Pulmonary arterial hypertension associated with human immunodeficiency
virus" and "The epidemiology and pathogenesis of pulmonary arterial hypertension
(Group 1)", section on 'Drugs and toxins'.)
• Portal hypertension – Portal hypertension and portovenous shunts can cause PH,
apparently by altering circulating vasoactive substance(s) in the blood [20,21].
● Lung disease – Acute and chronic parenchymal pulmonary disease can lead to PH.
Examples include pneumonia, bronchopulmonary dysplasia, acute respiratory distress

syndrome, interstitial lung disease, and cystic fibrosis. (See "Pulmonary hypertension
due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Treatment
and prognosis" and "Acute respiratory distress syndrome: Epidemiology,
pathophysiology, pathology, and etiology in adults", section on 'Consequences' and
"Cystic fibrosis: Clinical manifestations of pulmonary disease", section on 'Pulmonary
hypertension'.)
● Sickle cell disease (SCD) – PH occurs in approximately 10 percent of adult patients with
SCD; a similar percentage of children have an increased tricuspid regurgitant jet
velocity, although this finding does not always correlate with increased PVR at cardiac
catheterization. The biology of PH in SCD is not clear. The following factors may be
involved: endothelial injury, chronic inflammation, hypercoagulability, intravascular
hemolysis, and altered bioavailability of nitric oxide. Elevated left heart pressure from
diastolic dysfunction may also contribute. (See "Pulmonary hypertension associated
with sickle cell disease".)
● Chronic thromboembolic disease – Physical occlusion of pulmonary blood vessels

reduces the cross-sectional area of the vascular bed. Vasoconstriction and pathologic
remodeling in adjacent areas of the circulation further increases PVR [22]. (See
"Epidemiology, pathogenesis, clinical manifestations and diagnosis of chronic
thromboembolic pulmonary hypertension".)
● Systemic disease – A number of systemic diseases are associated with PH, including
rheumatologic (eg, sarcoidosis, scleroderma, mixed connective tissue disease, systemic
lupus erythematosus), metabolic, endocrine, and oncologic diseases. [23]. (See "Clinical
manifestations and diagnosis of sarcoidosis" and "Overview of pulmonary
complications of systemic sclerosis (scleroderma)", section on 'Pulmonary vascular
disease' and "Pulmonary manifestations of systemic lupus erythematosus in adults",
section on 'Pulmonary hypertension'.)
● Genetic mutations – PH may occur in families, and genetic mutations are associated
with heritable PH (albeit with variable penetrance) ( table 2). These include mutations
in genes encoding bone morphogenetic protein receptor type II ( BMPR2), endoglin
( ENG), activin receptor-like kinase 1 ( ALK-1), eukaryotic translation initiation factor
2-alpha kinase 4 ( EIF2AK4), T-box 4 ( TBX4), SOX family transcription factor 17
( SOX17), multiple SMAD genes, and others [24-29]. Additional genes and pathways
implicated in PH will likely be discovered. (See "The epidemiology and pathogenesis of
pulmonary arterial hypertension (Group 1)", section on 'Genetic mutations'.)
● Cellular and molecular mechanisms – A variety of cellular and molecular mechanisms

have been invoked to explain this disorder: abnormalities of endothelium, imbalance of
endogenous vasoconstrictors and vasodilators, clonal expansion of abnormal
pulmonary vascular cells, epigenetic mechanisms, abnormal expression of proteases,

endogenous growth factors and/or their receptors, and other molecules. Abnormal
intracellular molecules involved with smooth muscle contraction/relaxation (eg, cyclic
guanosine monophosphate) and cellular growth may also play a role. The precise role
of these and other factors in causing pulmonary vascular remodeling is yet to be
defined [30]. (See "The epidemiology and pathogenesis of pulmonary arterial
hypertension (Group 1)".)
It is important to note, however, that many of these factors are insufficient to cause PH by
themselves. PH is considered by some to be analogous to cancer and a multiple hit
hypothesis has emerged.
CLASSIFICATION
Etiologic classification — The 2018 6th World Symposium on Pulmonary Hypertension

(WSPH) updated clinical classification of PH includes five disease categories based upon
etiology and mechanism ( table 1) [31]. There is considerable overlap in some these
disease categories; many aspects of PH physiology span across all categories, and some
varieties of PH in one category closely resemble those in other categories. In addition, some
of the groupings are quite broad and lack a consistent clinical or biologic theme (groups 1
and 5), while others are fairly tightly-themed (groups 2, 3, and 4).
It has long been appreciated that the WSPH classification is insufficient for pediatric PH,
which often is related to fetal and developmental abnormalities and can have very different
clinical characteristics from that seen in older patients [13].
Despite its limitations, the WSPH classification does correspond to the categories of patients
included in targeted PH pharmacologic therapy trials (nearly all of which have included only
adult patients), which inform treatment decisions. Most large drug trials have investigated
group 1 PH (ie, pulmonary arterial hypertension [PAH], especially idiopathic PAH [including
heritable PAH] and PAH associated with collagen vascular disease or congenital heart
disease). By contrast, there are very few large trials involving patients with group 2 to 4 PH.
(See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary
hypertension-specific therapy" and "Pulmonary hypertension in children: Management and
prognosis", section on 'Specific agents for targeted PH therapy'.)
Transient versus persistent/progressive — Pediatric PH can be categorized according to

whether, based on the natural history of the underlying etiology, the PH typically resolves
over time (transient PH) or whether it tends to persist and/or worsen over time
(persistent/progressive PH):

● Transient PH – Examples of transient PH include [2,32]:
• Persistent PH of the newborn (see "Persistent pulmonary hypertension of the

newborn (PPHN): Clinical features and diagnosis")
• PH associated with congenital diaphragmatic hernia (see "Congenital diaphragmatic

hernia (CDH) in the neonate: Clinical features and diagnosis")
• PH associated with bronchopulmonary dysplasia, which typically improves gradually

but may persist (see "Bronchopulmonary dysplasia (BPD): Clinical features and
diagnosis")
• PH associated with acute pulmonary disease (eg, acute respiratory distress

syndrome) (see "Acute respiratory distress syndrome: Clinical features, diagnosis,
and complications in adults")
• Flow-related PH associated with cardiac shunting defects that are corrected in

infancy; however, in some cases, PH may persist after repair
It is important to recognize, however, that while these disorders are usually transient,
they can be associated with severe and life-threatening PH in the acute setting and may
require aggressive PH treatment and supportive therapy.
● Persistent/progressive PH – Examples of persistent/progressive PH include:
• Idiopathic/heritable PH
• PH associated with congenital cardiac shunting defects, particularly if repaired late
• PH associated with chronic pulmonary disease (eg, cystic fibrosis, interstitial lung
disease) (see "Classification of diffuse lung disease (interstitial lung disease) in
infants and children" and "Cystic fibrosis: Clinical manifestations of pulmonary
disease", section on 'Pulmonary hypertension')
• PH associated with sickle cell disease (SCD) (see "Pulmonary hypertension

associated with sickle cell disease")
Functional classification — Functional capacity in patients with PH is classified according to

the World Health Organization functional classification system ( table 3). However, like the
etiologic classification system, this system has considerable limitations in pediatric patients
in that it lacks developmentally appropriate and objective indicators of symptoms that can be
used in infants and children [2]. Exercise testing is often used to determine the functional
class in adults with PH; however, the lack of exercise standards for children <8 years make it
difficult to place young children in the World Health Organization classification.

The proposed Panama functional classification system attempts to provide age-specific

criteria for pediatric patients; however, this system requires validation [33].
EPIDEMIOLOGY
Pediatric PH is a rare condition with an estimated prevalence of approximately 3 to 20 cases

per one million children [32,34,35]. The prevalence varies according to age, with the highest
prevalence in infants <12 months old. Most cases of PH in infancy are secondary to lung
disease (ie, bronchopulmonary dysplasia-related PH and persistent pulmonary hypertension
of the newborn [PPHN]). (See "Pulmonary hypertension associated with bronchopulmonary
dysplasia" and "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features
and diagnosis".)
COMMON TYPES OF PULMONARY HYPERTENSION IN CHILDREN
Virtually all types of PH included in the 2018 6th World Symposium on Pulmonary
Hypertension (WSPH) classification can be observed in pediatric patients, though some
categories are exceedingly uncommon in childhood ( table 1). The most common types of
persistent/progressive PH in children are PH associated with congenital heart disease, PH
due to lung disease, and idiopathic/heritable PH [32,36,37]. Transient forms of PH, such as
persistent PH of the newborn and PH related to congenital diaphragmatic hernia, are also
relatively common [32]. PH is well described in children with collagen vascular disease, liver
disease, and acute thromboembolism, but these diseases are rare causes of PH in children
[36].
Persistent pulmonary hypertension of the newborn — Persistent PH of the newborn is

usually transient in nature [32]. This is discussed separately. (See "Persistent pulmonary
hypertension of the newborn (PPHN): Clinical features and diagnosis".)
Congenital heart disease — Only a small minority of patients with congenital heart disease
develop clinically significant PH. The two broad categories of congenital heart disease that
can cause PH include shunting lesions and left heart disease associated with elevated left
atrial pressure (LAp).
● Systemic-to-pulmonary shunting – By definition, PH occurs in any defect that by

virtue of its size and location exposes the pulmonary circulation to systemic-level
arterial pressure. Large ventricular septal defects are the most common example of
this. In infants with such lesions, the right ventricle (RV) is usually well adapted to high
pressure and, thus, the elevated pulmonary artery pressure (PAP), per se, is of little
consequence in the short term, though they may have symptoms of congestive heart
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failure. (See "Isolated ventricular septal defects (VSDs) in infants and children: Anatomy,
clinical features, and diagnosis".)
From the point of view of the pulmonary circulation, the greater significance of
unrepaired high-pressure shunting defects is that, during the first year or two, the
patient may develop high pulmonary vascular resistance (PVR) and pulmonary
hypertensive vascular disease, which can be irreversible and progressive [17]. PH can
persist and increase in patients after closure of intracardiac shunts, especially when
closed late. If PVR increases to systemic or greater levels, unrepaired defects that are
typically acyanotic (eg, ventricular septal defect, patent ductus arteriosus, atrial septal
defect) may become cyanotic by virtue of shunt reversal. This is referred to as
Eisenmenger syndrome. In addition to cyanosis, potential complications of
Eisenmenger syndrome include stroke, renal insufficiency, hypertrophic
osteoarthropathy, polycythemia, and thrombocytopenia [38]. Eisenmenger syndrome is
discussed in greater detail separately. (See "Pulmonary hypertension with congenital
heart disease: Clinical manifestations and diagnosis".)
Timely repair of high-pressure shunting defects is therefore of great importance. By

contrast, atrial septal defects are associated with low-pressure shunting (at least
initially) and they very infrequently lead to PH during childhood; when PH develops, it
typically occurs only after the first two decades of life [17]. Unlike ventricular septal
defects and patent ductus arteriosus, the timing of atrial septal defect repair (when
indicated) is usually after the first year of life. (See "Isolated atrial septal defects (ASDs)
in children: Management and outcome".)
● Left heart disease – Conditions that increase LAp (eg, mitral valve disease,
noncompliance of the left ventricle), can also cause PH; however, these are not common
in childhood [39]. The magnitude of elevation of PAP is highly variable: In some
patients, PAP is increased only to the same degree as the LAp but, in a substantial
minority, PAP is increased to a much greater degree compared with LAp [39].
● Pulmonary vein stenosis – Pulmonary vein stenosis is an uncommon cause of PH. It is

a rare disease that may be idiopathic or may be associated with total or partial
anomalous pulmonary venous return or prematurity [40]. This form of PH is almost
entirely unique to pediatric patients, with young infants most commonly affected. It is
rarely seen in adults except as a complication after catheter ablation for atrial
fibrillation. (See "Total anomalous pulmonary venous connection", section on 'Outcome'
and "Atrial fibrillation: Catheter ablation", section on 'Pulmonary vein stenosis' and
"Partial anomalous pulmonary venous return".)
Lung disease — Bronchopulmonary dysplasia is the most notable diagnostic entity in this
category [41]. Maldevelopment of and acquired injury to pulmonary blood vessels underlies
PH in this setting, and the vascular bed is especially prone to vasoconstriction with viral
infection or other stresses [11]. Most patients with PH due to bronchopulmonary dysplasia
are only mildly to moderately affected, especially when healthy, and PAP generally falls with
growth and development [42,43]. However, when PH is severe and persistent in this patient
population, it is associated with considerable morbidity and mortality [44]. An additional
etiology for PH in formerly preterm children is pulmonary vein stenosis, which can coexist
with bronchopulmonary dysplasia or develop in those with little lung disease [5]; the
pathobiology of this is not understood. (See "Pulmonary hypertension associated with
bronchopulmonary dysplasia".)
Many other types of acute and chronic lung disease in children may be complicated by PH.
These conditions are reviewed in detail separately:
● Congenital diaphragmatic hernia (see "Congenital diaphragmatic hernia (CDH) in the

neonate: Clinical features and diagnosis")
● Interstitial lung disease (see "Approach to the infant and child with diffuse lung disease
(interstitial lung disease)")
● Acute respiratory distress syndrome (see "Acute respiratory distress syndrome:

Epidemiology, pathophysiology, pathology, and etiology in adults", section on
'Consequences')
● Pneumonia (see "Community-acquired pneumonia in children: Clinical features and

diagnosis")
● Cystic fibrosis (see "Cystic fibrosis: Clinical manifestations of pulmonary disease",

section on 'Pulmonary hypertension')
Idiopathic/heritable pulmonary hypertension — Idiopathic and heritable PH are classified

together since they are clinically indistinguishable. Heritable PH includes patients with a
known PH genetic mutation and those with a family history of PH. Idiopathic PH refers to
patients with PH in whom no underlying cause has been identified. Heritable PH is likely
underdiagnosed, and some patients with idiopathic PH may actually have genetic causes of
their disease. [32,35].
Syndromes — PH is associated with a large number of chromosomal abnormalities,

syndromes, and complex, multiorgan diseases. In data from pediatric PH registries, 12 to 17
percent of children had underlying chromosomal or undefined syndromes [32,36,37]. Down
syndrome is the most common disorder in this category; others include DiGeorge, Pierre-
Robin, and Noonan syndromes [2,32,36,45]. However, the number of conditions associated
with PH is growing and too numerous to comprehensively list here. In patients with these
conditions, PH may develop as a result of cardiac or pulmonary disease associated with the

syndrome (eg, airway abnormalities, chronic aspiration, disordered breathing, restrictive

lung disease from neuromuscular weakness or scoliosis) or may be due to genetic factors
resulting from chromosomal abnormalities. PH is likely multifactorial in many cases.
CLINICAL FEATURES
The presentation of PH varies considerably based upon:
● Age of the patient

● Presence or absence of associated medical conditions
● Severity of the PH
● Right ventricular (RV) function
Signs and symptoms of PH, when present, may include [35,36,46]:
● Dyspnea with exertion

● Fatigue
● Syncope (usually with exertion)
● Cyanosis (with exertion or at rest)
● Failure to thrive
● Cough
● Chest pain
● Heart failure (uncommon)
Mildly or even moderately elevated pulmonary artery pressure (PAP) may cause no or only
subtle symptoms, especially in the sedentary. Symptoms may be more notable if there is a
supervening infection or other stressor. In one study, the average time from onset of
symptoms to diagnosis was approximately 17 months [36].
The degree of symptoms depends in large part on how well the RV adapts to the increased
pressure load. Some patients (especially those with PH since birth) develop RV hypertrophy
and have preserved RV contractile function. Such individuals may be relatively asymptomatic
for many years despite very high PAP. In other patients with similarly elevated PAP, the RV
adapts poorly, and reduced systolic and diastolic function limit cardiac output at exercise and
even rest.
The physical examination may be unremarkable, especially with only modestly increased PAP.
With RV dilation, there may be a left parasternal heave. The second heart sound (S2) may be
narrowly split (or single), with an increased pulmonic component ( movie 1), but, even with
markedly elevated PAP, this may escape detection. A systolic murmur of tricuspid
regurgitation or diastolic murmur of pulmonary regurgitation may be present with severely

elevated RV pressure. Hepatomegaly and peripheral edema generally indicate RV

dysfunction and may not be present even with severe PH.
Typical presenting symptoms and physical findings in the most common types of pediatric
PH are as follows:
● PH associated with congenital heart disease – The clinical features depend on the
specific defect and type of repair/palliation:
• Unrepaired cardiac shunting lesions – Cyanosis and polycythemia may be the

presenting signs of unrepaired cardiac shunting lesions with high pulmonary
vascular resistance (PVR). However, PAP and PVR can be markedly elevated, even in
patients with normal oxygen saturation. (See "Pulmonary hypertension with
congenital heart disease: Clinical manifestations and diagnosis", section on 'Clinical
manifestations'.)
• Cavopulmonary palliation – In patients with single-ventricle heart disease (eg,

hypoplastic left heart disease) who have undergone cavopulmonary palliation (ie,
Fontan or bidirectional Glen palliation), signs and symptoms of PH include poor
exercise tolerance, peripheral edema, pleural effusions, and protein-losing
enteropathy. (See "Management of complications in patients with Fontan
circulation", section on 'Cardiovascular complications'.)
● PH associated with lung disease — In patients with PH due to underlying lung

disease, the clinical presentation is largely determined by the primary disease, and the
impact of PH may be difficult to assess. Clinically significant elevations in RV pressure
can result in RV systolic dysfunction (usually demonstrated by echocardiography) with
consequent poor systemic perfusion and/or a tendency to retain fluid. On the other
hand, difficulty with gas exchange alone does not necessarily imply a significant role for
PH.
● Idiopathic/heritable PH — Idiopathic/heritable PH typically presents in previously

healthy ambulatory children. These patients may have no or only subtle symptoms
initially. Thus, idiopathic PH tends to be diagnosed at a relatively late stage in children.
EVALUATION
The initial evaluation for PH consists of:
● Electrocardiography
● Brain natriuretic peptide (BNP) level
● Chest radiograph

● Echocardiography
Echocardiography has a high sensitivity to identify patients with clinically important PH [47].
Cardiac catheterization is the gold standard for diagnosis of PH as it affords the most
accurate measure of pulmonary artery pressure (PAP) and provides additional valuable
information (eg, estimates of cardiac output, atrial pressures, response to pulmonary
vasodilators); however, this invasive test is not always necessary during the initial evaluation.
Additional testing is performed to evaluate functional capacity, better evaluate right ventricle
(RV) size and function (if not adequately assessed with echocardiography), and identify the
underlying etiology of PH if a cause is not identified in the initial evaluation. The diagnostic
evaluation is guided by the clinical findings. A thorough cardiopulmonary assessment is
required in all patients. For patients without a known predisposing condition (ie, idiopathic
PH), a comprehensive evaluation is required.
The findings on echocardiography, cardiac catheterization, and other tests are integrated
with assessment of functional class ( table 3) and degree of symptoms to determine the
severity of illness ( table 4).
History and physical examination — A complete history and physical examination should
be performed with particular attention to the following:
● Associated disease(s)
● Symptoms referable to the cardiovascular system (eg, easy fatigability, syncope, and
chest pain)
● Birth and neonatal history
● Family history of PH or of early death possibly due to cardiovascular disease
● History of residence at high altitude
● Signs of congenital cardiac disease or RV dilation and/or dysfunction – Left parasternal

heave, pathologic second heart sound (S2) ( movie 1), systolic or diastolic murmurs,
and hepatomegaly and peripheral edema
● Airway anomalies, chest wall deformity, or other signs of pulmonary disease
● Signs of other systemic disease (eg, telangiectasia)
Electrocardiography — The electrocardiogram is abnormal in most, but not all, patients

with moderate to severe PH [48]. Characteristic findings include RV hypertrophy
( waveform 1) and/or RV strain (eg, ST-T wave abnormalities in the inferior leads); less
commonly, right atrial enlargement may be noted ( waveform 1). However, these findings

are somewhat nonspecific and the electrocardiogram alone is insufficiently sensitive to serve
as a screen for PH.
BNP and NT-proBNP — Trending BNP levels can be a useful component of globally
assessing the patient's clinical course and monitoring response to treatment. BNP and N-
terminal pro-BNP (NT-proBNP) are biomarkers that are commonly used to assess severity
and monitor response to therapy in children and adults with heart failure. BNP is elevated in
patients with PH and may have prognostic value; however, data in pediatric patients are
limited [49-52]. In addition, an elevated BNP level does not distinguish between left and RV
failure. (See "Natriuretic peptide measurement in non-heart failure settings", section on
'Pulmonary hypertension'.)
Chest radiograph — Dilation of the main and proximal branch pulmonary arteries is a
common finding in patients with severe PH. Cardiomegaly suggests RV dysfunction and
dilation. Pulmonary edema may be present with heart failure (even if the RV is the failing
chamber) but also raises the possibility of pulmonary venous obstruction. If present,
pulmonary parenchymal disease is often apparent on the chest radiograph; this finding
should prompt consideration of chest computed tomography (CT). (See 'Additional testing'
below.)
Echocardiography — Echocardiography is the most helpful test in the initial assessment and
follow-up of patients with PH. It provides the following information [53]:
● Identification of structural cardiac lesions.
● Estimation of RV pressure – The most accurate echocardiographic method for

measuring RV (and hence pulmonary artery) systolic pressure is to determine the
velocity of the tricuspid regurgitant jet. However, not all patients have appreciable
tricuspid regurgitant and, even for those who do, careful interrogation of the jet is
required. Lacking an adequate tricuspid regurgitant jet, the position of the
interventricular septum at end systole may be helpful. The septal position provides only
a rough estimate of RV systolic pressure, and accurate quantification is not possible
without a tricuspid regurgitant jet [54]. High RV pressure is also suggested if right-to-
left shunting is seen across communications that normally shunt left-to-right (eg,
ventricular septal defect, patent ductus arteriosus, atrial septal defect). (See
"Echocardiographic assessment of the right heart", section on 'Pulmonary artery
pressure'.)
● Assessment of RV systolic function – RV systolic function can be qualitatively assessed

with echocardiogram, as can RV free wall thickness and cavity size (although magnetic
resonance imaging [MRI] more accurately measures the variables) [55].

● Assessment of valve regurgitation – Tricuspid (and less commonly, pulmonary valve)

regurgitation may be revealed.
Cardiac catheterization — Cardiac catheterization is the gold standard for diagnosis of PH;
however, it is not always necessary during the initial evaluation. Because it is an invasive
procedure that carries risks, cardiac catheterization is sometimes deferred until initiation of
targeted PH therapy is under consideration. (See "Pulmonary hypertension in children:
Management and prognosis", section on 'Targeted pulmonary hypertension therapy'.)
● Indications – Cardiac catheterization should generally be performed prior to initiation

of targeted PH therapy, with certain exceptions (eg, critically ill children who require
immediate empiric therapy) [2,56]. In addition, cardiac catheterization may be
performed in the following settings:
• When noninvasive testing is inadequate or nondiagnostic
• Follow-up of patients on targeted therapy
• In patients with systemic-to-pulmonary shunts to assess operability (although this is

infrequently required, especially in the first year of life)
• In patients undergoing evaluation for heart or heart-lung transplantation to assess

suitability for transplantation
● Information provided by catheterization – Compared with echocardiography, cardiac

catheterization:
• Provides a more accurate measurement of PAP
• Provides additional hemodynamic measurements (eg, cardiac output, atrial

pressures, pulmonary capillary wedge pressure)
• Allows vasoreactivity testing (ie, measurement of the response to vasodilators, such

as inhaled nitric oxide)
• Allows measurement of flow through shunt lesions
• In some cases, interventions can be performed to close shunting lesions (eg, device
closure of atrial septal defect, coiling of aortopulmonary collaterals)
• Can demonstrate abnormally shaped and distributed pulmonary arteries or stenosis

of large pulmonary arteries; however, the morphology of the small pulmonary
arteries has not proven to be a robust prognostic indicator [57]

● Acute vasoreactivity testing (AVT) – AVT is a particularly important component of the

cardiac catheterization in children with PH as it informs prognosis and can guide
therapy (eg, reactive patients are often treated with calcium channel blockers)
[56,58,59]. (See "Pulmonary hypertension in children: Management and prognosis",
section on 'Reactive acute vasoreactivity testing'.)
AVT involves the administration of a short-acting vasodilator (typically inhaled nitric

oxide) followed by measurement of the hemodynamic response. The criteria used to
identify "reactivity" on AVT in pediatrics have differed somewhat between centers and
among published studies [1,2,9,59]. The Pediatric Task Force of the 2018 6th World
Symposium on Pulmonary Hypertension (WSPH) suggested that "reactivity" be defined
by a decrease in mean PAP by at least 10 mmHg to a value of <40 mmHg with no
decrease in cardiac output [1]. Alternative criteria define reactivity as a ≥20 percent
decrease in mean PAP with a decreased ratio of systemic to pulmonary vascular
resistance (PVR) and unchanged or increased cardiac index [60]. An international
registry study found that the Pediatric Task Force definition more accurately identified
patients who could be successfully treated with calcium channel blockers compared
with other AVT criteria or the judgement of the treating clinician [59].
Other specific details of AVT are beyond the scope of this topic review and are discussed
separately. (See "Clinical features and diagnosis of pulmonary hypertension of unclear
etiology in adults", section on 'Right heart catheterization'.)
● Procedural risks – The main disadvantages of cardiac catheterization are the invasive
nature of the procedure, its inherent risks, and the need for general anesthesia or
sedation. Cardiac catheterizations in children with PH should be performed in centers
with experience and expertise in management of PH patients. In this setting, the risks
associated with the procedure are low, except for the most compromised patients
[61,62]. The risk of cardiac arrest is 0.8 to 2 percent, and the risk of pulmonary
hypertensive crisis is approximately 5 percent [2,61,63]. (See "Complications of
diagnostic cardiac catheterization".)
Additional testing — Additional testing is performed to better evaluate cardiac and

pulmonary function, assess the patient's functional capacity, and identify the underlying
etiology of PH if a cause is not identified in the initial evaluation. The diagnostic evaluation is
guided by the initial clinical findings.
● Cardiac MRI – Cardiac MRI more accurately quantifies RV size and ejection fraction
than does echocardiography. Some cardiac structural abnormalities (eg, abnormally
connected pulmonary veins) are also better defined on MRI than on echocardiography.
Also, pulmonary blood flow and cardiac output can be measured using this modality.

The need for sedation or even general anesthesia limits the use of this modality in
younger children.
● Six-minute walk test – This test of functional capacity, when applied according to strict
protocol, provides a useful estimate of cardiopulmonary capacity [64]. It is routinely
used by many practitioners for longitudinal follow-up of patients who are
approximately seven years of age and older. In younger children, testing is generally
not feasible, because of inability to cooperate with testing and lack of normative
reference values. Cardiopulmonary exercise testing is used less often in children with
PH, is more expensive, and requires more expertise in interpretation. (See "Exercise
testing in children and adolescents: Principles and clinical application", section on
'Idiopathic pulmonary arterial hypertension'.)
● Pulmonary function tests – Pulmonary function tests are performed to identify and
characterize underlying lung disease that may be contributing to PH. (See "Overview of
pulmonary function testing in children".)
● Chest CT scan – For children with clinical and/or radiographic findings suggestive of
parenchymal lung disease, chest CT with contrast can be helpful in the diagnostic
evaluation. Chest CT with contrast can also reveal large and small airways disease,
pulmonary emboli, and pulmonary vein stenosis. If pulmonary embolus is suspected,
formal CT pulmonary angiography should be performed (rather than a simple contrast
study). Chest CT can also suggest (but not confirm) the diagnosis of pulmonary veno-
occlusive disease [65]. (See "Approach to the infant and child with diffuse lung disease
(interstitial lung disease)", section on 'Computed tomography' and "Epidemiology,
pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive
disease/pulmonary capillary hemangiomatosis in adults", section on 'Computed
tomography'.)
● Polysomnography – For patients with clinical suspicion for upper airway obstruction or
sleep-disordered breathing, polysomnography may be warranted [66]. (See "Evaluation
of suspected obstructive sleep apnea in children".)
● Pulmonary perfusion scan – Nuclear lung scintigraphy or pulmonary

ventilation/perfusion scanning is routinely used in many centers for initial evaluation of
patients with PH. The primary reason for this testing is to detect evidence of chronic
pulmonary thromboemboli, although perfusion abnormalities are also seen with
pulmonary vein stenosis and multiple large pulmonary arterial stenoses.
Ventilation/perfusion scan may be performed if the suspected etiology for PH is
multiple pulmonary emboli. Since this is an exceedingly uncommon cause of PH in
pediatric patients, the ventilation/perfusion scan is a low-yield test in the pediatric
population. It has a high sensitivity but low specificity due to variable perfusion in
hypertensive lungs and/or pulmonary vein obstruction. CT angiography is the preferred

imaging modality for detecting acute pulmonary thromboembolism.
● Genetic testing – For children with idiopathic PH or a suggestive family history, genetic
testing for mutations associated with PH ( table 2) should be discussed with the
patient and parents during the diagnostic work up [2,52]. Initially, studies to identify
causative mutations in the affected child are undertaken by analyzing a panel of
selected candidate genes. Subsequent testing can be offered to family members if a
definitive mutation is identified. Given rapid progress in molecular diagnostics, follow-
up genetic counseling for PH patients and relatives is suggested during ongoing care.
Mutations in the gene encoding the transforming growth factor B cell surface receptor
( BMPR2) are noted in 70 percent of patients with heritable PH and 10 to 40 percent of
those with idiopathic PH [52,67-69]. These genes display autosomal dominant
inheritance with variable penetrance. Other mutations have been identified in patients
with PH associated with hereditary hemorrhagic telangiectasia and other forms of
pulmonary arterial hypertension (PAH) ( table 2) [70-73]. Genetic mutations are more
commonly identified in patients with childhood-onset idiopathic PAH compared with
adult-onset (35 percent versus 11 percent, respectively) [74].
● Lung biopsy – Lung biopsy is not a routine part of PH evaluation, partly due to its
invasive nature and associated morbidity but more importantly because it seldom
informs prognosis and therapy. Certain forms of diffuse lung disease may be
associated with PH and require diagnosis through lung biopsy. These are discussed in
greater detail separately. (See "Approach to the infant and child with diffuse lung
disease (interstitial lung disease)", section on 'Lung biopsy'.)
● Other tests – Other tests may be warranted based upon individual clinical findings or if
the etiology of PH remains uncertain after the initial evaluation (eg, patients with
apparently idiopathic PH). These include:
• Liver function tests and hepatic ultrasound to identify portal vein abnormalities
(portal atresia or porto-systemic shunts)
• HIV testing (although PH with HIV is rare in pediatric patients [1])
• Screening for autoimmune/inflammatory disorders (eg, erythrocyte sedimentation
rate and/or C-reactive protein, antinuclear antibodies, rheumatoid factor)
• Thyroid function tests
• Coagulation studies and thrombophilia evaluation
DIAGNOSIS

A presumptive diagnosis of PH can be established on the basis of echocardiography showing

quantitatively or qualitatively elevated right ventricular [RV] pressure. Definitive diagnosis of
PH requires cardiac catheterization; however, because this test is invasive, it is sometimes
deferred until initiation of targeted PH therapy is under consideration. The diagnosis of PH is
confirmed if mean pulmonary artery pressure (PAP) is >20 mmHg. (See 'Definition' above and
'Echocardiography' above and 'Cardiac catheterization' above.)
Specific diagnostic criteria for the different 2018 6th World Symposium on Pulmonary
Hypertension (WSPH) classes of PH are reviewed in detail separately. However, it is important
to note that the WSPH classification system has limitations in pediatric patients, as previously
discussed. (See 'Classification' above and "Clinical features and diagnosis of pulmonary
hypertension of unclear etiology in adults", section on 'Diagnosis'.)
DIFFERENTIAL DIAGNOSIS
The differential diagnosis of PH is broad, given the variable presenting signs and symptoms.
Other causes of undue dyspnea with exertion (which is the most common presenting
symptom in older children with PH) include structural heart disease, cardiomyopathy,
myocarditis, pericarditis, endocarditis, endocrine disorders (eg, hypothyroidism), postural
orthostatic tachycardia syndrome, lung disease (eg, asthma), malignancy, renal disease, liver
disease, viral syndrome, anemia, and psychiatric disorders (eg, depression, anxiety). The
clinical history and physical examination can distinguish some of these conditions from PH;
however, a formal cardiac evaluation including echocardiography is ultimately required to
make the diagnosis.
The differential diagnosis of dyspnea in children is described in greater detail separately.

(See "Causes of acute respiratory distress in children".)
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Pulmonary
hypertension in children".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have

about a given condition. These articles are best for patients who want a general overview
and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are
longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th
grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to
print or email these topics to your patients. (You can also locate patient education articles on
a variety of subjects by searching on "patient education" and the keyword[s] of interest.)
● Basics topic (see "Patient education: Pulmonary hypertension (The Basics)")
SUMMARY AND RECOMMENDATIONS
● Definition – Pulmonary hypertension (PH) is a disease characterized by elevated

pulmonary artery pressure (PAP), which may result in right ventricular (RV) failure. For
children and infants >3 months old, the definition of PH is the same as in adults: mean
PAP >20 mmHg at sea level. (See 'Definition' above.)
This definition has several limitations:
• It does not address infants ≤3 months old

• It fails to account for the impact PAP has on the RV
• It does not reflect whether the high PAP is due to an abnormal pulmonary vascular
bed, increased pulmonary blood flow, or increased pulmonary venous pressure
• It fails to account for the fact that pulmonary hypertensive vascular disease (PHVD)
can occur with PAP <20 mmHg
• It may not reflect the PAP during conditions other than those at the time of PAP
measurement.
● Causes and classification – Causes of PH are summarized in the table ( table 1). In
children, PH is usually associated with underlying cardiac or lung disease (eg,
congenital heart disease, bronchopulmonary dysplasia). PH may also be idiopathic or
familial. Other causes of PH are rare in childhood. (See 'Common types of pulmonary
hypertension in children' above.)
PH is classified according to etiology/mechanism ( table 1) and functional capacity

( table 3); however, these classification systems have important limitations in
pediatric patients, as discussed above. (See 'Classification' above.)
● Evaluation

• Referral – The diagnostic evaluation of PH in pediatric patients should be carried

out by or in close collaboration with practitioners with considerable experience and
expertise in this area. Early referral is critical since treatment for many types of PH is
less effective if provided at a late stage of the disease. (See 'Referral' above.)
• Initial testing – The initial evaluation for PH consists of (see 'Evaluation' above):
- A complete history and physical examination (see 'History and physical

examination' above)
- Electrocardiography (see 'Electrocardiography' above)
- Brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP) level (see
'BNP and NT-proBNP' above)
- Chest radiograph (see 'Chest radiograph' above)
- Cardiac echocardiography(see 'Echocardiography' above)
This testing has a high sensitivity to identify patients with clinically important PH.
• Cardiac catheterization – Cardiac catheterization is the gold standard for diagnosis

of PH as it affords the most accurate measure of PAP and provides additional
valuable information; however, it is not always necessary during the initial
evaluation. Because it is an invasive procedure that carries risks, cardiac
catheterization is sometimes deferred until initiation of targeted PH therapy is under
consideration. (See 'Cardiac catheterization' above.)
• Additional testing – Additional testing is performed to evaluate functional capacity,

better evaluate RV size and function (if not adequately assessed with
echocardiography), and identify the underlying etiology of PH if a cause is not
identified in the initial evaluation. The diagnostic evaluation is guided by the clinical
findings. A thorough cardiopulmonary assessment is required in all patients. For
patients without a known predisposing condition, a comprehensive evaluation is
required. (See 'Additional testing' above.)
● Diagnosis – A presumptive diagnosis of PH can be established with echocardiography

showing quantitatively or qualitatively elevated RV pressure. Definitive diagnosis of PH
requires cardiac catheterization; mean PAP >20 mmHg confirms the diagnosis. (See
'Diagnosis' above.)
The findings on echocardiography, cardiac catheterization, and other tests are

integrated with assessment of functional class ( table 3) and degree of symptoms to
determine the severity of illness ( table 4). (See 'Evaluation' above.)
● Differential diagnosis – The differential diagnosis of PH is broad, given the variable

presenting signs and symptoms. (See 'Differential diagnosis' above.)

ACKNOWLEDGMENT
The UpToDate editorial staff acknowledges Thomas Kulik, MD, now deceased, who
contributed to an earlier version of this topic review.
Use of UpToDate is subject to the Terms of Use.
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paediatric and adult pulmonary arterial hypertension: occurrence and prognostic value
when comparing three response criteria. Eur Heart J 2011; 32:3137.
59. Douwes JM, Humpl T, Bonnet D, et al. Acute Vasodilator Response in Pediatric
Pulmonary Arterial Hypertension: Current Clinical Practice From the TOPP Registry. J Am
Coll Cardiol 2016; 67:1312.
60. Barst RJ, Maislin G, Fishman AP. Vasodilator therapy for primary pulmonary
hypertension in children. Circulation 1999; 99:1197.
61. O'Byrne ML, Kennedy KF, Kanter JP, et al. Risk Factors for Major Early Adverse Events
Related to Cardiac Catheterization in Children and Young Adults With Pulmonary
Hypertension: An Analysis of Data From the IMPACT (Improving Adult and Congenital
Treatment) Registry. J Am Heart Assoc 2018; 7.
62. Rosenzweig EB, Bates A, Mullen MP, et al. Cardiac Catheterization and Hemodynamics in
a Multicenter Cohort of Children with Pulmonary Hypertension. Ann Am Thorac Soc
2022; 19:1000.
63. Beghetti M, Schulze-Neick I, Berger RM, et al. Haemodynamic characterisation and heart
catheterisation complications in children with pulmonary hypertension: Insights from
the Global TOPP Registry (tracking outcomes and practice in paediatric pulmonary
hypertension). Int J Cardiol 2016; 203:325.
64. Douwes JM, Hegeman AK, van der Krieke MB, et al. Six-minute walking distance and
decrease in oxygen saturation during the six-minute walk test in pediatric pulmonary
arterial hypertension. Int J Cardiol 2016; 202:34.
65. Resten A, Maitre S, Humbert M, et al. Pulmonary hypertension: CT of the chest in

pulmonary venoocclusive disease. AJR Am J Roentgenol 2004; 183:65.
66. Ismail K, Roberts K, Manning P, et al. OSA and pulmonary hypertension: time for a new
look. Chest 2015; 147:847.
67. International PPH Consortium, Lane KB, Machado RD, et al. Heterozygous germline
mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary

hypertension. Nat Genet 2000; 26:81.

68. Deng Z, Morse JH, Slager SL, et al. Familial primary pulmonary hypertension (gene PPH1)
is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum
Genet 2000; 67:737.
69. Soubrier F, Chung WK, Machado R, et al. Genetics and genomics of pulmonary arterial
hypertension. J Am Coll Cardiol 2013; 62:D13.
70. Smoot LB, Obler D, McElhinney DB, et al. Clinical features of pulmonary arterial
hypertension in young people with an ALK1 mutation and hereditary haemorrhagic
telangiectasia. Arch Dis Child 2009; 94:506.
71. Austin ED, Ma L, LeDuc C, et al. Whole exome sequencing to identify a novel gene
(caveolin-1) associated with human pulmonary arterial hypertension. Circ Cardiovasc
Genet 2012; 5:336.
72. Eyries M, Montani D, Girerd B, et al. EIF2AK4 mutations cause pulmonary veno-occlusive
disease, a recessive form of pulmonary hypertension. Nat Genet 2014; 46:65.
73. Best DH, Sumner KL, Austin ED, et al. EIF2AK4 mutations in pulmonary capillary
hemangiomatosis. Chest 2014; 145:231.
74. Welch CL, Chung WK. Genetics and Other Omics in Pediatric Pulmonary Arterial
Hypertension. Chest 2020; 157:1287.
Topic 17234 Version 15.0

GRAPHICS
Clinical classification of pulmonary hypertension
Group 1 - Pulmonary arterial hypertension (PAH)

1.1 Idiopathic:
1.1.1 Non-responders at vasoreactivity testing
1.1.2 Acute responders at vasoreactivity testing
1.2 Heritable*
1.3 Associated with drugs and toxins*
1.4 Associated with:
1.4.1 Connective tissue disease
1.4.2 HIV infection
1.4.3 Portal hypertension
1.4.4 Congenital heart disease
1.4.5 Schistosomiasis
1.5 PAH with features of venous/capillary (PVOD/PCH) involvement
1.6 Persistent PH of the newborn
Group 2 - PH associated with left heart disease
2.1 Heart failure:
2.1.1 with preserved ejection fraction
2.1.2 with reduced or mildly reduced ejection fraction ¶
2.2 Valvular heart disease
2.3 Congenital/acquired cardiovascular conditions leading to post-capillary PH
Group 3 - PH associated with lung diseases and/or hypoxia

3.1 Obstructive lung disease or emphysema
3.2 Restrictive lung disease
3.3 Lung disease with mixed restrictive/obstructive pattern
3.4 Hypoventilation syndromes
3.5 Hypoxia without lung disease (eg, high altitude)
3.6 Developmental lung disorders
Group 4 - PH associated with pulmonary artery obstructions

4.1 Chronic thrombo-embolic PH
4.2 Other pulmonary artery obstructions Δ

Group 5 - PH with unclear and/or multifactorial mechanisms

5.1 Haematological disorders ◊
5.2 Systemic disorders §
5.3 Metabolic disorders ¥
5.4 Chronic renal failure with or without haemodialysis
5.5 Pulmonary tumour thrombotic microangiopathy
5.6 Fibrosing mediastinitis
PAH: pulmonary arterial hypertension; HIV: human immunodeficiency virus; PVOD: pulmonary veno-
occlusive disease; PCH: pulmonary capillary haemangiomatosis; PH: pulmonary hypertension.
* Patients with heritable PAH or PAH associated with drugs and toxins might be acute responders.
¶ Left ventricular ejection fraction for heart failure with reduced ejection fraction: ≤40%; for heart
failure with mildly reduced ejection fraction: 41 to 49%.
Δ Other causes of pulmonary artery obstructions include: sarcomas (high or intermediate grade or
angiosarcoma), other malignant tumours (eg, renal carcinoma, uterine carcinoma, germ-cell tumours
of the testis), non-malignant tumours (eg, uterine leiomyoma), arteritis without connective tissue
disease, congenital pulmonary arterial stenoses, and hydatidosis.
◊ Including inherited and acquired chronic haemolytic anaemia and chronic myeloproliferative
disorders.
§ Including sarcoidosis, pulmonary Langerhans's cell histiocytosis, and neurofibromatosis type 1.
¥ Including glycogen storage diseases and Gaucher disease.
Reproduced with permission of the © European Society of Cardiology & European Respiratory Society 2023: European
Respiratory Journal 61 (1) 2200879; DOI: 10.1183/13993003.00879-2022. Published 6 January 2023.
Graphic 66348 Version 11.0

Genetic mutations associated with pulmonary hypertension
Gene Disease Inheritance Function
BMPR2 IPAH/HPAH Autosomal Type II receptor of TGF-beta family of

dominant signaling molecules
ALK1 HHT Autosomal Type I receptor of TGF-beta family

dominant
ENG HHT Autosomal Type II receptor of TGF-beta family

dominant
SMAD1 IPAH/HPAH N/A Signal transduction molecule
SMAD4 HHT Autosomal Signal transduction molecule

dominant
SMAD9 IPAH/HPAH Autosomal Signal transduction molecule

dominant
KCNK3 IPAH/HPAH Autosomal pH-sensitive potassium channel

dominant
CAV1 IPAH/HPAH Autosomal Membrane protein required for

dominant formation of caveolae
EIF2AK4 PVOD/PCH Autosomal Kinase involved in control of

recessive angiogenesis
SOX17 IPAH/HPAH Autosomal Sox family transcription factor

dominant
TBX4 Small patellar Autosomal T-box transcription factor

syndrome dominant
IPAH: idiopathic pulmonary arterial hypertension; HPAH: heritable pulmonary arterial hypertension;
TGF: transcription growth factor; HHT: hereditary hemorrhagic telangiectasia; PVOD: pulmonary veno-
occlusive disease; PCH: pulmonary capillary hemangiomatosis.

World Health Organization (WHO) functional classification for pulmonary

hypertension
Class WHO functional classification
I Patients with PH but without resulting limitations of physical activity. Ordinary physical
activity does not cause undue fatigue or dyspnea, chest pain, or heart syncope.
II Patients with PH resulting in slight limitation of physical activity. They are comfortable
at rest. Ordinary physical activity results in undue fatigue or dyspnea, chest pain, or
heart syncope.
III Patients with PH resulting in marked limitation of physical activity. They are
comfortable at rest. Less than ordinary physical activity causes undue fatigue or
dyspnea, chest pain, or heart syncope.
IV Patients with PH resulting in inability to carry on any physical activity without

symptoms. These patients manifest signs of right heart failure. Dyspnea and/or fatigue
may be present even at rest. Discomfort is increased by physical activity.
PH: pulmonary hypertension; WHO: World Health Organization.
Data from: Rich S. Primary pulmonary hypertension: executive summary. Evian, France. World Health Organization, 1998.

Severity assessment of pulmonary hypertension in pediatric patients
Clinical variable Lower risk High risk
Clinical evidence of RV failure No Yes
Progressive symptoms No Yes
WHO functional class I to II III to IV
Growth Normal Poor weight gain and/or growth

failure
Syncope None Recurrent
BNP/NT-proBNP Minimally elevated Markedly elevated and/or rising
6MWD (for children >6 years old) ≥350 meters <350 meters
Echocardiography Minimal RV enlargement and/or Considerable RA/RV

dysfunction enlargement
Reduced LV size
Increased RV/LV ratio
Reduced TAPSE
Low RV FAC
Pericardial effusion
Hemodynamics measured by Systemic CI >3.0 L/min/m 2 Systemic CI <2.5 L/min/m 2

cardiac catheterization
Systemic venous saturation mRAP >10 mmHg
>65%
PVRI >20 WU•m 2
Reactive AVT
Systemic venous saturation
<60%
PACI <0.85 mL/mmHg/m 2
This stable summarizes the approach to severity assessment in children with PH based upon the
clinical criteria listed above. Categorization as lower versus high risk is not precise and is based in part
on the clinical judgment of the treating clinician. For the lower-risk category, all standard criteria
should generally be met; for the high-risk category, patients typically meet multiple criteria, though all
criteria need not be met. Some patients have intermediate findings and do not fall clearly into a
lower- or high-risk category.
This table is intended for use in conjunction with additional UpToDate content on PH in children. Refer
to UpToDate topics on the evaluation and management of PH in children for additional details.
RV: right ventricle; WHO: World Health Organization; BNP: brain natriuretic peptide; NT-proBNP: N-
terminal pro-BNP; 6MWD: six-minute walk distance; RA: right atrium; LV: left ventricle; TAPSE: tricuspid
annular plane systolic excursion; FAC: fractional area change; CI: cardiac index; AVT: acute
vasoreactivity testing; mRAP: mean right atrial pressure; PVRI: pulmonary vascular resistance indexed

to body surface area; WU: Wood unit; PACI: pulmonary arterial compliance index; PH: pulmonary
hypertension.

Electrocardiogram in a young child with pulmonary hypertension
ECG obtained in a 3 year-old child with pulmonary hypertension. Findings include:

1. Right atrial enlargement (arrow): The P wave in lead II is >2.5 mm. This is sometimes referred to
as "P pulmonale."
2. Right ventricular hypertrophy: Tall R waves in V1 and deep S waves in V5 and V6 suggest RVH. R
wave amplitude in V1 is 30 mm (upper limit of normal for this age is 20 mm).
3. Rightward axis deviation: QRS axis in this child is 125 (upper limit of normal for this age is 110).
ECG: electrocardiogram; RVH: right ventricular hypertrophy.

Contributor Disclosures
Mary P Mullen, MD, PhD No relevant financial relationship(s) with ineligible companies to
disclose. David R Fulton, MD No relevant financial relationship(s) with ineligible companies to
disclose. George B Mallory, MD No relevant financial relationship(s) with ineligible companies to
disclose. Carrie Armsby, MD, MPH No relevant financial relationship(s) with ineligible companies to
disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.
Conflict of interest policy

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21/2/24, 22:52 Pulmonary hypertension in children: Classification, evaluation, and diagnosis - UpToDate

Official reprint from UpToDate®

Pulmonary hypertension in children: Classification,

Literature review current through: Jan 2024.

Pulmonary hypertension (PH) is a disease characterized by elevated pulmonary artery

The classification, evaluation, and diagnosis of PH in children are reviewed here.

Persistent PH of the newborn, PH associated with bronchopulmonary dysplasia, the

https://www.uptodate.com/contents/pulmonary-hypertension-in-children-classification-evaluation-and-diagnosis/print?search=pulmonary hyperte… 1/37

● (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in

The diagnostic evaluation of PH in pediatric patients should be carried out by or in close

The following terms are used throughout this topic:

● Pulmonary hypertension (PH) – PH refers to elevated pulmonary artery pressure (PAP;

● Pulmonary vascular resistance (PVR) – PVR is a measurement of the resistance in the

● Pulmonary arterial hypertension (PAH) – PAH refers to elevation of the pressure in

● Pulmonary venous hypertension – Pulmonary venous hypertension refers to

● Pulmonary hypertensive vascular disease (PHVD) – PHVD (previously called

In addition to the PAP value, the following questions should be addressed:

● Does the elevation in PAP reflect an abnormal pulmonary vascular bed or is it

● To what degree does the PH impact right ventricle (RV) function?

The following sections discuss these issues in greater detail:

https://www.uptodate.com/contents/pulmonary-hypertension-in-children-classification-evaluation-and-diagnosis/print?search=pulmonary hyperte… 3/37

● Cardiac shunting lesions or left heart disease – Patients with systemic-to-pulmonary

● Conditions at time of measurement – Measurements of PAP in the echocardiography

https://www.uptodate.com/contents/pulmonary-hypertension-in-children-classification-evaluation-and-diagnosis/print?search=pulmonary hyperte… 4/37

PHYSIOLOGY AND PATHOGENESIS

● Decreased cross-sectional area of the pulmonary vascular bed

As previously noted, pulmonary vascular resistance (PVR) provides an estimation of whether

● Anatomic changes – Pulmonary hypertensive vascular disease (PHVD; previously

https://www.uptodate.com/contents/pulmonary-hypertension-in-children-classification-evaluation-and-diagnosis/print?search=pulmonary hyperte… 5/37

A comprehensive mechanistic understanding of why and how disease occurs in pulmonary

● Developmental abnormalities – Abnormal pulmonary vascular development,

• Alveolar hypoxia – Examples of extrinsic causes of alveolar hypoxia include living at

• Increased mechanical forces – Congenital intracardiac shunting lesions and/or left

https://www.uptodate.com/contents/pulmonary-hypertension-in-children-classification-evaluation-and-diagnosis/print?search=pulmonary hyperte… 6/37

● Chronic thromboembolic disease – Physical occlusion of pulmonary blood vessels

● Cellular and molecular mechanisms – A variety of cellular and molecular mechanisms

pulmonary vascular cells, epigenetic mechanisms, abnormal expression of proteases,

Etiologic classification — The 2018 6th World Symposium on Pulmonary Hypertension

Transient versus persistent/progressive — Pediatric PH can be categorized according to

https://www.uptodate.com/contents/pulmonary-hypertension-in-children-classification-evaluation-and-diagnosis/print?search=pulmonary hyperte… 8/37

● Transient PH – Examples of transient PH include [2,32]:

• Persistent PH of the newborn (see "Persistent pulmonary hypertension of the

• PH associated with congenital diaphragmatic hernia (see "Congenital diaphragmatic

• PH associated with bronchopulmonary dysplasia, which typically improves gradually

• PH associated with acute pulmonary disease (eg, acute respiratory distress

• Flow-related PH associated with cardiac shunting defects that are corrected in

● Persistent/progressive PH – Examples of persistent/progressive PH include:

• PH associated with congenital cardiac shunting defects, particularly if repaired late

• PH associated with sickle cell disease (SCD) (see "Pulmonary hypertension

Functional classification — Functional capacity in patients with PH is classified according to

https://www.uptodate.com/contents/pulmonary-hypertension-in-children-classification-evaluation-and-diagnosis/print?search=pulmonary hyperte… 9/37

The proposed Panama functional classification system attempts to provide age-specific

Pediatric PH is a rare condition with an estimated prevalence of approximately 3 to 20 cases

COMMON TYPES OF PULMONARY HYPERTENSION IN CHILDREN

Persistent pulmonary hypertension of the newborn — Persistent PH of the newborn is

● Systemic-to-pulmonary shunting – By definition, PH occurs in any defect that by

https://www.uptodate.com/contents/pulmonary-hypertension-in-children-classification-evaluation-and-diagnosis/print?search=pulmonary hypert… 10/37

Timely repair of high-pressure shunting defects is therefore of great importance. By

● Pulmonary vein stenosis – Pulmonary vein stenosis is an uncommon cause of PH. It is

● Congenital diaphragmatic hernia (see "Congenital diaphragmatic hernia (CDH) in the

● Acute respiratory distress syndrome (see "Acute respiratory distress syndrome:

● Pneumonia (see "Community-acquired pneumonia in children: Clinical features and

● Cystic fibrosis (see "Cystic fibrosis: Clinical manifestations of pulmonary disease",