Persistent Pulmonary Hypertension

Introduction

Persistent pulmonary hypertension of the newborn (PPHN) can be seen with many cardiopulmonary disorders with an incidence ranging from 0.4 to 6.8 per 1000 live births and 5.4 per 1000 live births in late preterm infants. The etiology of PPHN in preterm infants is usually secondary to hypoxemic respiratory failure related to significant lung pathology soon after birth such as respiratory distress syndrome (RDS), preterm premature rupture of membranes (PPROM), or oligohydramnios causing pulmonary hypoplasia. In the term infant, PPHN is most commonly seen with conditions such as congenital diaphragmatic hernia (CDH), meconium aspiration syndrome (MAS), and transient tachypnea of the newborn (TTN). Mortality of all newborns with PPHN has been reported at 7.6% and 10.7% infants with severe PPHN. Surviving infants with PPHN have increased risk of long-term morbidities, including ~25% neurodevelopmental impairment at 2 years. PPHN is defined as the failure to achieve or sustain the normal decrease in pulmonary vascular resistance (PVR) at birth. PPHN can produce severe respiratory distress and hypoxemia secondary to severe pulmonary vascular disease remodeling ( Fig. 47.1 ) in term and near-term infants. Chronic pulmonary hypertension is associated with lung diseases such as bronchopulmonary dysplasia (BPD) and CDH and is a common complication of congenital heart disease. This chapter will review the pathophysiology of PPHN, diagnosis and clinical treatment of newborns with severe PPHN disease, and outcome data.

Normal Fetal Pulmonary Vascular Development and Transition at Birth

During fetal life, placental vascular resistance is low and PVR is high. This state of physiologic pulmonary hypertension is needed to maintain the patterns of blood flow that support gas exchange by the placenta. In the human fetus, only 10% to 20% of the combined ventricular output is directed to the pulmonary vascular bed with most of the right ventricular output crossing the ductus arteriosus to the descending aorta. Throughout gestation both pulmonary artery pressure (PAP) and pulmonary blood flow progressively increase with the developing growth of the lung vasculature. Despite the marked increase in cross-sectional area of the pulmonary vascular bed, high PVR is maintained and even increases during gestation when corrected for gestational age. This persistent elevation in PVR throughout gestation is mediated by changes in fetal pulmonary vessel vasoregulation. Initially, the fetal pulmonary circulation is poorly responsive to diverse stimuli, but reactivity to vasoconstrictor and vasodilator agonists increases during late gestation. This normal maturational change in vasoregulation leads to increased vascular tone and sustained elevations in PVR in late gestation.

The elevated PVR throughout fetal life is maintained by many factors, such as mechanical compression of pulmonary blood vessels from fluid-filled alveoli, hypoxic pulmonary vasoconstriction, increased production of circulating vasoconstrictors (endothelin-1, thromboxane, and leukotrienes), low levels of vasodilator products (nitric oxide [NO] and prostacyclin [PgI ₂ ]), and abnormal smooth muscle cell reactivity leading to enhanced myogenic tone. The vasodilatory response to oxygen and acetylcholine emerges in late gestation.

At birth, a rapid and dramatic decrease in PVR redirects half of the combined ventricular output to the lung and increases pulmonary blood flow by 8- to 10-fold. Increased pulmonary blood flow increases pulmonary venous return and left atrial pressure, promoting functional closure of the one-way valve of the foramen ovale. Clamping of the umbilical cord removes the low-resistance placental circulation, thus increasing systemic vascular resistance (SVR). The largest drop in PVR and pulmonary arterial pressure (PAP) occurs shortly after birth, although both will continue to fall during the first few months of life until levels are similar to that of typical adult circulation pressure levels. As PVR falls below systemic levels, blood flow through the patent ductus arteriosus reverses. During the first several hours of life the ductus arteriosus functionally closes, largely in response to the increased oxygen tension of the newborn. This effectively separates the pulmonary and systemic circulations and establishes the normal postnatal circulatory pattern.

These normal transitional changes in the pulmonary vasculature are initiated by ventilation of the lung and an increase in oxygen tension at birth and are mediated by alterations in several vasoactive compounds prior to birth and immediately following delivery. The fetus prepares for the extra-uterine transition late in gestation by increasing pulmonary vascular expression of NO synthases and soluble guanylate cyclase (sGC) ( Fig. 47.2 ). At the time of birth, pulmonary endothelial NO production increases markedly, partly as a response to increased oxygen tension and shear stress. NO exerts its actions through sGC to increase the levels of cyclic guanosine monophosphate (cGMP), a central mediator responsible for vascular relaxation. Phosphodiesterase 5 (PDE5) catalyzes the breakdown of cGMP and, similarly to sGC, exhibits peak expression and activity in the immediate newborn period. The arachidonic acid–prostacyclin pathway also plays a significant role in the pulmonary vascular transition at birth (see Fig. 47.2 ). The enzyme cyclooxygenase acts on arachidonic acid to produce prostaglandin endoperoxides. Prostaglandins activate adenylate cyclase to increase cyclic adenosine monophosphate (cAMP) concentrations in vascular smooth muscle cells, which, similarly to increases in cGMP concentrations, leads to vasorelaxation. Phosphodiesterase 3 A catalyzes the breakdown of cAMP.

Pathophysiology

Infants who develop PPHN after birth display failure of the normal cardiopulmonary transition. The first reports of PPHN described term newborns with profound hypoxemia who lacked radiographic evidence of parenchymal lung disease and echocardiographic evidence of structural cardiac disease. In these patients, refractory hypoxemia was caused by sustained elevations of PVR and low pulmonary blood flow leading to right-to-left extrapulmonary shunting of deoxygenated blood across the patent ductus arteriosus or patent foramen ovale. Because of the persistently elevated PVR and blood flow through these “fetal shunts,” the term persistent fetal circulation was originally used to describe these findings.

PPHN physiology can complicate the clinical course of term or preterm neonates with many different causes of hypoxemic cardiopulmonary failure, such as meconium aspiration, sepsis, pneumonia, asphyxia, CDH, and respiratory distress syndrome. As a result, the term persistent pulmonary hypertension of the newborn now denotes a syndrome characterized by sustained elevation of PVR and hypoxemia due to right-to-left extrapulmonary shunting of blood flow across the ductus arteriosus or foramen ovale. Hypoxemic respiratory failure in term infants is often presumed to be secondary to PPHN physiology, however, many hypoxemic newborns lack echocardiographic findings of extrapulmonary shunting across the PDA or PFO. Thus, PPHN describes hypoxemic newborns with evidence of extrapulmonary shunting.

The clinical presentation of infants with PPHN includes labile hypoxemia and often includes the findings of a gradient in oxygen saturations between pre-ductal (right upper extremity) and post-ductal values greater than 10%. The presence of a pre- and post-ductal oxygen saturation gradient over 10% suggests the presence of extrapulmonary right-to-left shunting at the ductus arteriosus. Infants with PPHN can have wide swings in arterial oxygen saturation levels, which is due to rapid changes in pulmonary blood flow and right-to-left shunting associated with acute changes in PVR in response to minimal stimulation. Physical exam findings are often subtle but may include a loud second heart sound and a systolic murmur of tricuspid regurgitation. A chest radiograph is often helpful to differentiate primary parenchymal lung disease (meconium aspiration syndrome [MAS] or respiratory distress syndrome [RDS]) from other non-pulmonary etiologies of PPHN. Typical radiographic findings in idiopathic PPHN include pulmonary vascular oligemia, normal or slight hyperinflation, and a lack parenchymal infiltrates. In primary PPHN, the degree of hypoxemia is disproportionate to the severity of radiographic findings of lung disease.

PPHN is associated with many diverse cardiopulmonary disorders ( Table 47.1 ) with an incidence ranging from 0.4 to 6.8 per 1000 live births and 5.4 per 1000 live births in late preterm infants. One year mortality of all newborns with PPHN has been reported at 7.6%, rising to 10.7% for infants with severe PPHN. Surviving infants with PPHN are at increased risk of long-term morbidities, including ~25% neurodevelopmental impairment at 2 years.

In 2019 the Pediatric Task Force of the World Symposium on Pulmonary Hypertension (WSPH) updated the WSPH Classification of pulmonary hypertension to differentiate PPHN as an important cause of pediatric PH. Because of its specific anatomic and physiologic characteristics, PPHN was assigned a separate subcategory within WSPH Group 1, or pulmonary arterial hypertension, as Group 1.7. In Group 3 pulmonary hypertension (pulmonary hypertension due to lung disease or hypoxia), developmental lung diseases are specifically listed because of the important role that abnormal lung vascular growth plays in the pathogenesis of impaired lung development and pulmonary hypertension. CDH, BPD, and several other developmental lung disorders, such as surfactant protein deficiencies and alveolar capillary dysplasia (ACD), are now understood to be important causes of pulmonary hypertension in infants.

The etiology of PPHN is broad, but can generally be classified into one of three categories: (1) maladaptation: pulmonary vessels have normal structure and number but have abnormal vasoreactivity (respiratory distress syndrome [RDS], meconium aspiration syndrome [MAS], sepsis, or pneumonia); (2) excessive muscularization: increased smooth muscle cell thickness and abnormal distal extension of muscle into vessels that are usually not muscularized (chronic fetal hypoxia, idiopathic PPHN); and (3) underdevelopment: lung tissue hypoplasia associated with decreased pulmonary artery number (congenital diaphragmatic hernia [CDH], oligohydramnios) (see Table 47.1 ). There are many disorders associated with PPHN in the newborn period (see Table 47.1 ). Idiopathic PPHN is the least common, occurring in about 10% of cases. More commonly, PPHN is usually associated with an acute respiratory condition, such as meconium aspiration syndrome, respiratory distress syndrome, or pneumonia, and is referred to as secondary PPHN . This designation is imprecise, however, as many patients often have elevated PVR that involves overlapping categories. For example, infants with CDH-related PPHN may be due not only to underdevelopment of the pulmonary vasculature, but also to abnormal maladaptation and vasoreactivity, events that often culminate in chronic pulmonary vascular disease. Similarly, in infants with PPHN secondary to MAS the pulmonary vasculature can exhibit excessive muscularization of vessels in addition to abnormal vasoreactivity. In many cases it can be more difficult to separate chronic intrauterine remodeling from acute pulmonary vasoconstriction due to parenchymal lung disease.

Risk Factors

Based on the significant remodeling found in lethal cases of PPHN, intrauterine events have been presumed to affect pulmonary vascular growth, reactivity, and structure (see Fig. 47.1 ). Pulmonary vascular development in utero can be disrupted by environmental, placental, toxic, or other influences ( Fig. 47.3 ). Case-control surveillance studies indicate that maternal risk factors of black or Asian maternal race, elevated body mass index (>27 kg/m ² ), diabetes, and asthma predict a higher risk of PPHN. Neonatal risk factors include male sex, large for gestational age infants, birth by cesarean delivery, and delivery before 37 weeks’ gestation or after 41 weeks’ gestation.

Recent animal and epidemiologic studies also suggest that maternal exposures can alter fetal pulmonary vascular development and function. There are strong associations between PPHN and maternal smoking, and two classes of maternal medications, nonsteroidal anti-inflammatory drugs and selective serotonin receptor inhibitors, have also been implicated. Exposure to nonsteroidal anti-inflammatory drugs such as aspirin or ibuprofen during the third trimester can cause constriction of the fetal ductus arteriosus, which in turn can trigger pulmonary vascular remodeling and PPHN. Based on the findings of a recent epidemiologic study, the relationship is complex and may be dependent on the specific agent and the timing of exposure, however aspirin use during late pregnancy remains a consistent risk factor for PPHN. Use of selective serotonin receptor inhibitors during the last half of pregnancy has been associated with an increased incidence of PPHN in several population studies, although the severity of PPHN has not been well described, and other studies have not found this association. Maternal depression is a risk factor for adverse pregnancy outcomes, as such maternal physical and psychologic well-being remain the primary factors guiding antidepressant therapy during pregnancy and the postpartum period.

Several postnatal events can disrupt the perinatal transition and contribute to the pathogenesis of PPHN (see Fig. 47.3 ). Birth by elective cesarean delivery delays the decrease in pulmonary arterial pressure and increases the risk of PPHN, and delivery before 39 weeks’ gestation likely amplifies this effect. When compared with matched controls, infants with PPHN are more likely to have been born by cesarean delivery, born to diabetic mothers, mothers of advanced maternal age, mothers of Black race, or mothers with asthma or a high body mass index—in addition to being born before 37 weeks’ gestation. Perinatal asphyxia with resultant fetal hypoxemia, ischemia, acidosis, and cardiac ventricular dysfunction prevents the necessary perinatal adaptation, delays the normal decrease in PVR, and increases the risk of PPHN. Acute perinatal asphyxia is associated with reversible pulmonary vasoconstriction, while chronic in utero asphyxia can induce vascular remodeling that is less responsive to acute vasodilation.

The adoption of therapeutic hypothermia for management of neonatal encephalopathy in the term and near-term infant has led to concern that this therapy would increase risk of PPHN in asphyxiated infants. Deep levels of hypothermia (30°C to 32°C) have been shown to increase mean pulmonary arterial pressure in neonatal lambs and have been associated with increased use of extracorporeal membrane oxygenation (ECMO) and inhaled nitric oxide (iNO) in human studies. Furthermore, hypothermia shifts the oxygen dissociation curve to the left and decreases Pa O ₂ at a given peripheral capillary oxygen saturation (Sp O ₂ ). However, pooled analysis of randomized trials of standard therapeutic hypothermia (33.5°C) has not shown an increased incidence of PPHN (25% vs 20%) in treated infants.

Patients with severe hypoxemia who are not responding as expected to conventional therapies should be evaluated for developmental lung diseases associated with refractory PPHN. Children with Down syndrome (trisomy 21) commonly develop pulmonary hypertension in association with structural heart defects but also have a 10-fold increased risk of idiopathic PPHN. In a Dutch cohort, PPHN was documented in 5.2% of Down syndrome infants, and other studies have shown that Down syndrome infants are overrepresented in neonates requiring ECMO support. Polymorphisms of genes for bone morphogenetic protein receptor or other transforming growth factor β receptors, other critical growth factors, or vasoactive enzymes (e.g., NO synthase, phosphodiesterase) have not been shown to increase the risk of neonatal PPHN. Additional systematic evaluation for genetic etiologies of refractory or prolonged PPHN should include: inherited surfactant dysfunction disorders, such as SP-B/C or ATP-binding cassette A3 gene (ABCA3) deficiency ; genetic disruption of distal lung development, such as TTF-1 and Nkx 2.1; FOXF1 mutations leading to alveolar capillary dysplasia (ACD), T-Box transcription factor 4 gene (TBX4) ; genetic variants in corticotropin releasing hormone (CRH) receptor 1 and CRH-binding protein ; and inborn errors of metabolism, such as methylmalonic acidemia. Genotype analysis of neonates with PPHN have also identified polymorphisms in carbamoyl-phosphate synthase, a key urea cycle enzyme that maintains substrate availability for endogenous nitric oxide production and genetic variants for cortisol signaling ( CRHR1 and CRHBP ), as well as increased levels of 17-hydroxyprogesterone.

Abnormal Pulmonary Vasoregulation in PPHN

Disruptions of the NO–cGMP, prostacyclin–cAMP, and endothelin signaling pathways play an important role in the vascular abnormalities associated with PPHN. The NO–cGMP pathway has been a topic of particularly intense investigation in the last two decades. Decreased expression and activity of endothelial nitric oxide synthase (eNOS) has been documented in lamb models of chronic intrauterine pulmonary hypertension, and decreased eNOS expression has been found in umbilical venous endothelial cell cultures from human infants with meconium staining who developed PPHN. These important findings were rapidly followed by clinical testing of iNO, leading to its adoption as the primary vasodilator therapy for PPHN. However, numerous other signaling abnormalities limit the effect of endogenous or exogenous NO. In PPHN, expression and activity of soluble guanylate cyclase is decreased, and cGMP phosphodiesterase activity is increased, leading to lower cGMP levels and limitations of NO-induced vasodilation. Oxidant stress associated with vascular dysfunction and/or exposure to hyperoxia can oxidize and reduce soluble guanylate cyclase activity and increase cGMP phosphodiesterase activity, accentuating these vascular abnormalities.

Prostacyclin is important in the normal pulmonary vascular transition, although less is known about abnormal prostacyclin–cAMP signaling in PPHN. Data from animal models suggest reductions in prostacyclin synthesis and downstream adenylate cyclase responses, analogous to the abnormalities reported for NO–cGMP signaling. In addition, production of thromboxane, a vasoconstrictor arachidonic acid metabolite, plays a role in pulmonary hypertension produced by chronic hypoxia. Elevated levels of circulating endothelin 1 (ET-1), a potent vasoconstrictor, have been demonstrated in lambs and newborns with PPHN. Endothelin effects are mediated through two receptors: ET _A receptors on smooth muscle cells that mediate vasoconstriction and ET _B receptors on endothelial cells that mediate vasodilation. In PPHN, the balance of endothelin receptors is shifted to the vasoconstrictor (ET _A ) pathways. Endothelin may also affect vascular tone by increasing production of vasoconstrictor reactive oxygen species such as superoxide and hydrogen peroxide and by decreasing expression and activity of peroxisome proliferator–activated receptor γ, which maintains the vasodilatory balance in the fetal lung.

Disorders Associated With Pulmonary Hypertension at Birth