eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Cardiology

Pulmonary Hypertension, Persistent-Newborn

Author: Robin H Steinhorn, MD, Raymond and Hazel Speck Berry Professor of Pediatrics, Division Head of Neonatology, Associate Chair of Pediatrics, Northwestern University School of Medicine
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Updated: Sep 22, 2009

Introduction

Background

Pulmonary hypertension is a normal and necessary state for the fetus. Because the placenta, not the lungs, serves as the organ of gas exchange, most of the right ventricular output crosses the ductus arteriosus to the aorta, and only 5-10% of the combined ventricular output is directed to the pulmonary vascular bed. Multiple pathways appear to be involved in maintaining high pulmonary vascular tone prior to birth. Pulmonary vasoconstrictors in the normal fetus include low oxygen tension, endothelin-1, leukotrienes, and Rho kinase. Vasoconstriction is also promoted by low basal production of vasodilators, such as prostacyclin and nitric oxide (NO).

A dramatic cardiopulmonary transition occurs at birth, characterized by a rapid fall in pulmonary vascular resistance (PVR) and pulmonary artery pressure and a 10-fold rise in pulmonary blood flow. The most critical signals for these transitional changes are mechanical distension of the lung, a decrease in carbon dioxide tension, and an increase in oxygen tension in the lungs. The fetus prepares for this transition late in gestation by increasing pulmonary expression of nitric oxide synthases and soluble guanylate cyclase.

In some newborns, the normal decrease in pulmonary vascular tone does not occur, and the result is persistent pulmonary hypertension of the newborn (PPHN). Severe persistent pulmonary hypertension of the newborn has been estimated to occur in 2 per 1000 of live-born term infants, and some degree of pulmonary hypertension complicates the course of more than 10% of all neonates with respiratory failure.

Pathophysiology

Persistent pulmonary hypertension of the newborn is defined as the failure of the normal circulatory transition that occurs after birth. It is a syndrome characterized by marked pulmonary hypertension that causes hypoxemia and right-to-left extrapulmonary shunting of blood. Because a patent foramen ovale and patent ductus arteriosus are normally present early in life, elevated pulmonary vascular resistance in the newborn produces extrapulmonary shunting of blood, leading to severe and potentially unresponsive hypoxemia. With inadequate pulmonary perfusion, neonates are at risk for developing refractory hypoxemia, respiratory distress, and acidosis.

Respiratory failure and hypoxemia in the term newborn results from a heterogeneous group of disorders, and the therapeutic approach and response often depend on the underlying disease. Persistent pulmonary hypertension of the newborn can be generally characterized as one of 3 types: (1) the abnormally constricted pulmonary vasculature due to lung parenchymal diseases (eg, meconium aspiration syndrome, respiratory distress syndrome, pneumonia); (2) the lung with normal parenchyma and remodeled pulmonary vasculature, also known as idiopathic persistent pulmonary hypertension of the newborn; or (3) the hypoplastic vasculature as seen in congenital diaphragmatic hernia. 

Although idiopathic pulmonary hypertension is responsible for only 10-20% of all infants with persistent pulmonary hypertension of the newborn, severe cases are almost certainly affected by both parenchymal and vascular disease. An abnormally remodeled vasculature may develop in utero in response to prolonged fetal stress, hypoxia, and/or pulmonary hypertension. Excessive and peripheral muscularization of pulmonary arterioles can be seen in these cases.

Frequency

United States

Neonatal respiratory failure affects 2% of all life births, or nearly 80,000 newborns per year, and is responsible for nearly half of all neonatal deaths. Nearly one third of all infants with respiratory failure were born at term or near-term and are at especially high risk for persistent pulmonary hypertension of the newborn.

Recent data suggest that persistent pulmonary hypertension of the newborn occurs as often as 2-6 cases per 1000 live births. Persistent pulmonary hypertension of the newborn is a frequent complicating factor in the term or near-term newborn with parenchymal lung disease (eg, meconium aspiration syndrome, pneumonia).

Mortality/Morbidity

As recently as 15 years ago, the mortality rate for persistent pulmonary hypertension of the newborn was nearly 40%, and the prevalence of major neurologic disability was 15-60%.

The introduction of extracorporeal membrane oxygenation (ECMO) and other new therapies has had a major effect on reducing the mortality rate associated with persistent pulmonary hypertension of the newborn. In the United Kingdom, the effect of ECMO technology was studied in a randomized trial, the only one to use death as an endpoint.¹ The mortality rate decreased from approximately 60% in the group randomly assigned to receive conventional therapy to 30% for the group randomly assigned to receive ECMO.

If all available therapies are used, the mortality rate is less than 10%. However, the prevalence of major neurologic disabilities among surviving newborns remains approximately 20% or higher, even for infants with moderate pulmonary hypertension of the newborn.

Age

By definition, persistent pulmonary hypertension of the newborn a disorder of the newborn. However, pulmonary hypertension may complicate the course of older infants with chronic respiratory insufficiency due to bronchopulmonary dysplasia.

Clinical

History

Clinically, persistent pulmonary hypertension of the newborn (PPHN) is most often recognized in term or near term neonates but may infrequently occur in premature neonates. Persistent pulmonary hypertension of the newborn typically presents as respiratory distress and cyanosis within 6-12 hours of birth. Although persistent pulmonary hypertension of the newborn is often associated with perinatal distress, such as asphyxia, low Apgar scores, meconium staining, and other factors, idiopathic persistent pulmonary hypertension of the newborn can present without signs of acute perinatal distress. Marked lability in oxygenation is frequently part of the clinical history.

• The most common cause of persistent pulmonary hypertension of the newborn is meconium aspiration syndrome, which affects 25,000-30,000 infants, with 1000 deaths each year in the United States.
  
  

  

  Meconium aspiration. Serial radiographs in a newborn with uncomplicated meconium aspiration. Radiograph obtained shortly after birth shows ill-defined, predominantly perihilar opacities in the lungs; these are more severe on the right than on the left. The lungs are hyperexpanded. The neonate's heart size is within normal limits. The abnormalities on the initial chest radiograph, aside from the presence of an endotracheal tube and an umbilical artery catheter, are identical to those seen in severe cases of transient tachypnea of the newborn.

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  Meconium aspiration. Serial radiographs in a newborn with uncomplicated meconium aspiration. Radiograph obtained shortly after birth shows ill-defined, predominantly perihilar opacities in the lungs; these are more severe on the right than on the left. The lungs are hyperexpanded. The neonate's heart size is within normal limits. The abnormalities on the initial chest radiograph, aside from the presence of an endotracheal tube and an umbilical artery catheter, are identical to those seen in severe cases of transient tachypnea of the newborn.

  
  
  • Approximately 13% of all live births are complicated by meconium-stained fluid, but only 5% of infants who had this complication subsequently develop meconium aspiration syndrome.
  • Although the traditional belief is that aspiration occurs with the first breath after birth, in severely affected infants, aspiration most likely occurs in utero. Therefore, perinatal distress or meconium staining of the amniotic fluid may be part of the patient's antenatal history.
• Idiopathic persistent pulmonary hypertension of the newborn, or “black-lung” persistent pulmonary hypertension of the newborn, is the second most common etiology of persistent pulmonary hypertension of the newborn.
  • Evaluation of infants at autopsy shows clinically significant remodeling of their pulmonary vasculature, with vascular wall thickening and smooth muscle hyperplasia. Furthermore, the smooth muscle extends to the level of the intra-acinar arteries, which does not normally occur until late in the postnatal period.
  • One cause of idiopathic persistent pulmonary hypertension of the newborn is constriction of the fetal ductus arteriosus in utero because of exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) during the third trimester. Therefore, a history of NSAID use should be sought from the mother. Even if this history is negative, NSAIDs are frequently recovered from the meconium of infants with persistent pulmonary hypertension of the newborn.
  • Another recently reported association with idiopathic persistent pulmonary hypertension of the newborn is maternal use of selective serotonin reuptake inhibitors (SSRIs), particularly during the second trimester. However, the association between SSRI use and severe persistent pulmonary hypertension of the newborn is unclear.

Physical

• Persistent pulmonary hypertension of the newborn most typically affects infants who are phenotypically normal, although the syndrome occurs with higher frequency in newborns with Down syndrome.
• Upon initial examination, the primary finding is cyanosis, which is usually associated with tachypnea and respiratory distress. Cardiac examination may reveal a loud, single S2 sound or a harsh systolic murmur secondary to tricuspid regurgitation.
• The patient may have evidence of poor cardiac function and perfusion.

Causes

• The factors that produce antenatal vascular remodeling are less well understood. Genetic factors may increase susceptibility for pulmonary hypertension. Strong links between persistent pulmonary hypertension of the newborn and polymorphisms of the carbamoyl phosphate synthase gene have been reported. However, the importance of this finding is uncertain, and further work is needed in this area.
• One cause of idiopathic persistent pulmonary hypertension of the newborn is constriction of the fetal ductus arteriosus in utero, which can occur after exposure to NSAIDs during the third trimester. New data suggest that exposure to selective serotonin reuptake inhibitors (SSRI’s) during late gestation is associated with a 6-fold increase in the prevalence of persistent pulmonary hypertension of the newborn, although how many infants have severe disease is unclear.
• Newborn rats exposed in utero to fluoxetine develop pulmonary vascular remodeling, abnormal oxygenation, and higher mortality when compared with vehicle-treated controls. Because SSRIs have been reported to reduce pulmonary vascular remodeling in adult models of pulmonary hypertension, these findings highlight the unique nature of fetal pulmonary vascular development.
• Persistent pulmonary hypertension of the newborn is most commonly associated with 1 of 3 underlying etiologies. The first and most commonly encountered scenario is acute pulmonary vasoconstriction due to acute perinatal events, such as the following:
  • Alveolar hypoxia secondary to parenchymal lung disease, such as meconium aspiration syndrome, respiratory distress syndrome, or pneumonia
  • Hypoventilation resulting from asphyxia or other neurologic conditions
  • Hypothermia
  • Hypoglycemia
• The second cause, idiopathic persistent pulmonary hypertension of the newborn, is associated with normal chest radiography findings and no parenchymal lung disease. Newborns with idiopathic persistent pulmonary hypertension of the newborn present with pure vascular disease. Some clinicians refer to this syndrome as "black lung" persistent pulmonary hypertension of the newborn or "clear lung" persistent pulmonary hypertension of the newborn. This syndrome typically results from an abnormally remodeled pulmonary arterial bed, which perhaps secondary to chronic stress in utero. Other potential associations include maternal use of NSAIDs, such as ibuprofen or naproxen, or SSRIs in the last half of pregnancy
• Hypoplasia of the pulmonary vascular bed is a third cause of persistent pulmonary hypertension of the newborn.
  • Congenital diaphragmatic hernia is an abnormality of diaphragmatic development that allows the abdominal viscera to enter the chest and compress the lung.
  • The oligohydramnios sequence may produce pulmonary hypoplasia and associated persistent pulmonary hypertension of the newborn.
  • A congenital cystic adenomatoid malformation may lead to lung hypoplasia, although persistent pulmonary hypertension of the newborn is rarely associated with this malformation, even if the defect is large.

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