Persistent Pulmonary Hypertension of the Newborn

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DESCRIPTION

Persistent pulmonary hypertension of the newborn (PPHN) is a clinical syndrome due to failed transition to extrauterine life characterized by sustained elevation of pulmonary vascular resistance (PVR) and consequential hypoxemic respiratory failure.

EPIDEMIOLOGY

  • Incidence of 1.8 per 1,000 live newborns
  • Most commonly in term and near-term infants, although PPHN is increasingly recognized in extremely preterm infants
  • Males are affected more often than females.
  • Infection (30%) is the most common cause of PPHN, followed by meconium aspiration syndrome (MAS) (24%), idiopathic (20%), respiratory distress syndrome (RDS) (7%), and congenital diaphragmatic hernia (CDH) (6%).
  • Mortality from PPHN is estimated at 7–10%.

RISK FACTORS

Genetics

  • Recently, a few candidate genes have been identified as possible contributors to the pathogenesis of PPHN.
    • Such genetic variants include T-box transcription factor 4 gene (TBX4) and bone morphogenic protein receptor type 2 (BMPR2).
    • Other genes that may be associated with PPHN include carbamoyl phosphate synthetase 1 (CPS1), NOTCH3, SMAD9, tubulin tyrosine ligase-like family member 3 gene (TTLL3), and integrin subunit alpha M gene (ITGAM).
  • Other genetic disorders have increased risk for the development of PPHN.
    • Alveolar capillary dysplasia associated with misalignment of the pulmonary veins is a lethal genetic cause of PPHN in which there is abnormality in the air–blood interface, with increased distance between the alveolar epithelium and capillaries.
    • Genetic disorders of surfactant dysfunction have also been implicated, although they are rare and often lethal.
    • Infants with trisomy 21 are at increased risk of PPHN.

ETIOLOGY

  • Maladaptation of pulmonary vasculature:
    • MAS
    • RDS
    • Transient tachypnea of the newborn
    • Congenital pneumonia
    • Sepsis
    • Perinatal asphyxia/hypoxic ischemic encephalopathy
    • Polycythemia
    • High-output cardiac failure
  • Maldevelopment of pulmonary vasculature:
    • Pulmonary hypoplasia (premature prolonged rupture of membranes [PPROM], renal anomalies or obstruction)
    • CDH
    • Trisomy 21
    • Intrauterine growth restriction (IUGR)
    • Congenital heart disease
    • Premature closure of the ductus arteriosus
    • Maternal medication use (nonsteroidal anti-inflammatory drugs (NSAIDs) or selective serotonin reuptake inhibitors [SSRIs])
    • Maternal factors (smoking, obesity, diabetes)
  • Idiopathic PPHN

PATHOPHYSIOLOGY

  • There are multiple concurrent and interrelated processes that occur perinatally to facilitate the successful circulatory transition to extrauterine life. This cascade of events leads to appropriate decreases in PVR and increases in systemic vascular resistance (SVR).
  • Decreased PVR is due to active sodium absorption and clearance of alveolar fluid, ventilation and oxygenation at birth leading to pulmonary vasodilation and establishment of functional residual capacity, and shear stress with subsequent release of nitric oxide (NO) furthering pulmonary vasodilation.
  • Increased SVR follows the clamping of the umbilical cord by removing the low-resistance placental circulation.
  • Increased left atrial pressure due to increased SVR reverses flow across patent foramen ovale (PFO), leading to its closure.
  • Similarly, reduced PVR and increased SVR leads to reversal of flow and left-to-right shunting across the patent ductus arteriosus (PDA). Functional ductal closure occurs within minutes due to decreased placental prostaglandin E2 as well as increased arterial oxygen tension and increased endothelin-1 promoting vasoconstriction. Permanent closure occurs over the ensuing weeks with endothelial proliferation and fibrosis.
  • Disruption to, or failure of, this process results in persistent fetal circulation characterized by hypoxic vasoconstriction and acidosis secondary to elevated PVR, decreased pulmonary blood flow, as well as intrapulmonary and extrapulmonary right-to-left shunting.
  • Elevated PVR and increased right ventricular (RV) afterload leads to RV dysfunction and tricuspid regurgitation acutely, or RV hypertrophy chronically.
  • Extrapulmonary right-to-left (or bidirectional) shunting at the PDA and PFO delivers deoxygenated blood to the systemic circulation with subsequent hypoxia and acidosis.
  • Similarly, intrapulmonary shunting due to ventilation–perfusion (V/Q) mismatch worsens hypoxemia.
  • In severe PPHN, this may lead to RV dysfunction, RV dilation, and ultimately RV failure.
  • In addition to RV dysfunction, leftward bowing of the interventricular septum decreases left ventricular (LV) preload and leads to LV dysfunction, resulting in decreased cardiac output.
  • The resulting hypoxemia and acidosis worsen cardiac function and importantly are potent vasoconstrictors, which worsens PPHN, perpetuating the vicious cycle.

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