I. DEFINITION. Persistent pulmonary hypertension of the newborn (PPHN) reflects disruption of the normal perinatal fetal to neonatal circulatory transition. The disorder is characterized by sustained elevation in pulmonary vascular resistance (PVR) rather than the decrease in PVR that normally occurs at birth. Survivors of PPHN are at risk for adverse sequelae including chronic pulmonary disease and neurodevelopmental disabilities. Contemporary neonatal intensive care, including ventilator management, treatment with inhaled nitric oxide (iNO), and extracorporeal membrane oxygenation (ECMO), collectively have improved survival among infants with PPHN.

A. Perinatal circulatory transition. The normal perinatal circulatory transition is characterized by a rapid fall in PVR accompanying the first breath and a marked increase in systemic vascular resistance (SVR) associated with clamping of the umbilical cord. Circulating biochemical mediators released in response to increased arterial oxygen content and pH and lowered PaCO₂ cause constriction of the ductus arteriosus and vasorelaxation of the pulmonary circulation. These physiologic events raise SVR relative to PVR, cause functional closure of the foramen ovale, and signal the normal perinatal transition in pulmonary and systemic circulations. PPHN physiology mimics the fetal circulation in which PVR exceeds SVR and right-to-left hemodynamic shunting occurs through the foramen ovale and/or ductus arteriosus. Because of the similarity to the cardiovascular physiology of fetal life, PPHN also has been called “persistent fetal circulation.” Before birth, this circulatory configuration results in systemic delivery of oxygenated blood from the placental circulation; in postnatal life, it causes diminished pulmonary perfusion and systemic hypoxemia.

II. EPIDEMIOLOGIC ASSOCIATIONS. PPHN occurs at a rate of 1 to 2 per 1,000 live births and is most common among full-term and postterm infants. Perinatal risk factors reported in association with PPHN include meconiumstained amniotic fluid and maternal conditions such as fever, anemia, and pulmonary disease. Case-control studies of risk factors for PPHN suggest associations between PPHN and a number of antenatal and perinatal factors, including maternal diabetes mellitus, urinary tract infection during pregnancy, selective serotonin reuptake inhibitor (SSRI) consumption during pregnancy, and cesarean section delivery. Male infants and those of black or Hispanic race are also at increased risk for PPHN. Although mechanisms of antenatal pathogenesis remain uncertain, there are a number of additional perinatal and neonatal conditions that have well-established links with PPHN.

A. Severe fetal hypoxemia (“asphyxia”) is the most common associated diagnosis. Some speculate that prolonged fetal stress and hypoxemia lead to remodeling and abnormal muscularization of pulmonary arterioles. Acute birth asphyxia also causes release of vasoconstricting humoral factors and suppression of pulmonary vasodilators, thus contributing to pulmonary vasospasm.

B. Pulmonary parenchymal diseases, including surfactant deficiency, pneumonia, and aspiration syndromes, such as meconium aspiration, also are associated with increased risk of PPHN. In most such cases, the pulmonary hypertension is reversible, suggesting a vasospastic contribution; however, concomitant pulmonary vascular remodeling cannot be excluded. The risk of pulmonary hypertension appears to be greater when the fetus is of more advanced gestational age, suggesting that the stage of pulmonary vascular development might play a role in susceptibility to PPHN.

C. Abnormalities of pulmonary development contribute structurally to PPHN, either by pruning of the vascular tree, as occurs in congenital diaphragmatic hernia, Potter syndrome, and other forms of pulmonary parenchymal hypoplasia, or malalignment of pulmonary veins and arteries, as is seen in alveolar capillary dysplasia.

D. Myocardial dysfunction, myocarditis, intrauterine constriction of the ductus arteriosus, and several forms of congenital heart disease, including leftand right-sided obstructive lesions, can lead to pulmonary hypertension.

E. Pneumonia and/or sepsis of bacterial or viral origin can initiate PPHN. Underlying pathophysiologic mechanisms that contribute to pulmonary hypertension in this clinical setting include suppression of endogenous nitric oxide (NO) production, endotoxin-mediated myocardial depression, and pulmonary vasoconstriction associated with release of thromboxanes.

F. Although familial recurrence of PPHN is uncommon, genetic predisposition might play a role in PPHN risk. Infants with PPHN have low plasma levels of arginine and NO metabolites and also exhibit diminished endothelial nitric oxide synthase (eNOS) expression. Polymorphisms associated in case reports of PPHN involve several genes, including ABCA3, TMEM70 (mitochondrial), CRHR1, ACE, and SPINK5 (Netherton syndrome). Furthermore, PPHN associated with alveolar capillary dysplasia has been linked with mutation of FOXF1.

A. Pulmonary vascular remodeling is pathognomonic of idiopathic PPHN and has been reported among a series of infants with fatal PPHN. Abnormal muscularization of the normally nonmuscular intra-acinar arteries, with increased medial thickness of the larger muscular arteries, results in a decreased cross-sectional area of the pulmonary vascular bed and elevated PVR. Mechanisms leading to the vascular remodeling of PPHN are under investigation. One possible stimulus to pulmonary vascular remodeling is fetal hypoxemia. Humoral growth factors released by hypoxia-damaged endothelial cells promote vasoconstriction and overgrowth of the pulmonary vascular muscular media. Laboratory and limited clinical data suggest that vascular changes might also occur following fetal exposure to nonsteroidal anti-inflammatory agents that cause constriction of the fetal ductus arteriosus and associated fetal pulmonary overcirculation.

B. Pulmonary hypoplasia affects both alveolar and pulmonary arteriolar development. It may be seen as an isolated anomaly or with congenital diaphragmatic hernia, oligohydramnios syndrome, renal agenesis (i.e., Potter syndrome), or remodeling or vasoconstriction of impaired fetal breathing.

C. Reversible pulmonary vasospasm is the likely pathophysiologic mechanism among infants with nonfatal PPHN. The underlying disease process, the associated conditions, and the developmental stage of the host each appear to modulate the pathophysiologic response. Hypoxia induces profound pulmonary vasoconstriction, and this response is exaggerated by acidemia. Neural and humoral vasoactive substances each might contribute to the pathogenesis of PPHN, the response to hypoxemia, or both. These include factors associated with platelet activation and production of arachidonic acid metabolites. Suppression of endogenous NO, prostacyclin, or bradykinin production and release of thromboxanes (A₂ and its metabolite, B₂), and leukotrienes (C₄ and D₄), appear to mediate the increased PVR seen with sepsis and hypoxemia.

1. Right ventricular (RV) dysfunction can be caused by intrauterine constriction of the ductus arteriosus, which results in altered fetal hemodynamics, postnatal pulmonary hypertension, RV failure, and an atrial right-to-left shunt. Furthermore, RV failure resulting in altered diastolic compliance causes right-to-left atrial shunting, even in the absence of elevated PVR.

2. Left ventricular (LV) dysfunction causes pulmonary venous hypertension and secondary pulmonary arterial hypertension, often to suprasystemic levels, contributing to right-to-left hemodynamic shunting through the ductus arteriosus. Treating this form of pulmonary hypertension requires an approach that improves LV function rather than simply lowering PVR.

E. Mechanical factors that influence PVR include cardiac output and blood viscosity. Low cardiac output recruits fewer pulmonary arteriolar channels and raises PVR by this mechanism as well as by its primary effect of lowering mixed venous oxygen content. Hyperviscosity, associated with polycythemia, reduces pulmonary microvasculature perfusion.

IV. DIAGNOSIS. PPHN should be routinely considered in evaluating the cyanotic newborn.

A. Among cases of suspected PPHN, the most common alternative diagnoses are congenital heart disease, sepsis, and severe pulmonary parenchymal disease.

B. The infant with PPHN appears distressed and has a physical examination that is most remarkable for evidence of cyanosis. In some infants, the extent of cyanosis might be appreciably different between regions perfused by pre- and postductal vasculature. The cardiac examination is notable for a prominent precordial impulse, a single or narrowly split and accentuated second heart sound, and sometimes, a systolic murmur consistent with tricuspid regurgitation.

C. A gradient of 10% or more in oxygenation saturation between simultaneous preductal (right upper extremity) and postductal (lower extremity) arterial blood gas (ABG) values or transcutaneous oxygen saturation (SaO₂) measurements documents the presence of a ductus arteriosus right-to-left hemodynamic shunt and, in the absence of structural heart disease, suggests PPHN. Because a subset of infants with PPHN has closure of the ductus arteriosus and their hemodynamic shunting occurs only at the foramen ovale, the absence of differential cyanosis or SaO₂ does not exclude PPHN.

D. The chest radiograph usually appears normal or shows associated pulmonary parenchymal disease. The cardiothymic silhouette is normal, and pulmonary blood flow is normal or diminished.

E. The electrocardiogram (ECG) most commonly shows RV predominance that is within the range considered normal for age. Less commonly, the ECG might reveal signs of myocardial ischemia or infarction.

F. An echocardiographic study should be performed in all infants with suspected PPHN to document hemodynamic shunting, evaluate ventricular function, and exclude congenital heart disease. Color Doppler examination is useful to assess the presence of intracardiac or ductal hemodynamic shunting. Additional echocardiographic markers, such as tricuspid valve regurgitation or a ventricular septum that is flattened or bowed to the left, suggest pulmonary hypertension. Pulmonary artery pressure can be estimated using continuous-wave Doppler sampling of the velocity of the tricuspid regurgitation jet, if present.

G. Other diagnostic considerations. A number of disorders, some of which are associated with secondary pulmonary hypertension, may be misdiagnosed as PPHN. Therefore, an important aspect of the evaluation of the infant with presumed PPHN is to rule out competing conditions, including the following: