The first reports of PPHN described term newborns with profound hypoxemia who lacked radiographic evidence of parenchymal lung disease and echocardiography evidence of structural cardiac disease (Fig. 3A). In these patients, hypoxemia was caused by marked elevations of PVR leading to right-to-left extrapulmonary shunting of blood across the patent DA (PDA) or foramen ovale (FO) during the early postnatal period. Due to the persistence ofhigh PVR and blood flow through these fetal shunts, the term "persistent fetal circulation" was originally used to describe this group of patients. Consequently, it was recognized that this physiological pattern can complicate the clinical course of neonates with diverse causes of hypoxemic respiratory failure. As a result, the term PPHN has been considered as a syndrome, and is currently applied more broadly to include neonates that have a similar physiology in association with different cardiopulmonary disorders, such as meconium aspiration, sepsis, pneumonia, asphyxia, congenital diaphragmatic hernia, respiratory distress syndrome (RDS). Striking differences exist between these conditions, and mechanisms that contribute to high PVR can vary between these diseases. However, these disorders are included in the syndrome of PPHN due to common pathophysiological features, including sustained elevation of PVR leading to hypoxemia due to right-to-left extrapulmonary shunting of blood flow. In many clinical settings, hypoxemic respiratory failure in term newborns is often presumed to be associated with PPHN-type physiology; however, hypoxemic term newborns can lack echocardiography findings of extra-pulmonary shunting across the PDA or PFO. Thus, PPHN should be reserved to neonates in whom extrapulmonary shunting contributes to hypoxemia and impaired cardiopulmonary function. Recent estimates suggest an incidence for PPHN of 1.9/1000 live births, or an estimated 7400 cases/year (86).
PPHN-associated diseases are often classified within one of 3 categories: i) maladaptation: vessels are presumably of normal structural but have abnormal vasoreactivity; ii) excessive muscularization: increased smooth muscle thickness and increased distal extension of muscle to vessels which are usually non-muscular; and iii) underdevelopment: lung hypoplasia associated with decreased pulmonary artery number. This designation is, imprecise, however, and high PVR in most patients likely involve overlapping changes among these categories. For example, neonates with congenital diaphragmatic hernia are primarily classified as having vascular "underdevelopment" due to lung hypoplasia, yet lung histology of fatal cases typically shows marked muscularization of pulmonary arteries and, clinically, these patients respond to vasodilator therapy. Similarly, neonates with meconium aspiration often have clinical evidence of altered vasoreactivity, but often have muscularization at autopsy.
As described above, autopsy studies of fatal PPHN demonstrate severe hypertensive structural remodeling even in newborns who die shortly after birth, suggesting that many cases of severe disease are associated with chronic intrauterine stress (Fig. 3B). However, the exact intrauterine events that alter pulmonary vascular reactivity and structure are poorly understood. Epidemiologic studies have demonstrated strong associations between PPHN and maternal smoking and ingestion of cold remedies that include aspirin or other non-steroidal anti-inflammatory products (83). Since these agents can induce partial constriction of the DA ), it is possible that pulmonary hypertension due to DA narrowing contributes to PPHN (see below). Other perinatal stresses, including placenta previa and abruption, and asymmetric growth restriction, are associated with PPHN; however, most neonates who are exposed to these prenatal stresses do not develop PPHN. Circulating levels of L-arginine, the substrate for NO, are decreased in some newborns with PPHN, suggesting that impaired NO production may contribute to the pathophysiology of PPHN, as observed in experimental studies. It is possible that genetic factors increase susceptibility for pulmonary hypertension. A recent study reported strong links between PPHN and polymorphisms of the carbamoyl phosphate synthase gene (61). However, the importance of this finding is uncertain, and further work is needed in this area. Studies of adults with idiopathic primary pulmonary hypertension have identified abnormalities of bone morphogenetic protein receptor genes; whether polymorphisms of genes for the BMP or TGF-B receptors, other critical growth factors, vasoactive substances or other products increase the risk for some newborns to develop PPHN is unknown.
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