Abstract
Background
Persistent pulmonary hypertension in the newborn is associated with increased risk of cardiorespiratory failure, neurodevelopmental delay, and death.
Aim of review
The purpose of this article is to review normal and abnormal perinatal pulmonary vasculature adaptation and persistent pulmonary hypertension of the newborn, including etiology, pathophysiology, clinical manifestations, diagnostic methods, and treatment.
Key scientific concepts of review
Persistent pulmonary hypertension of the newborn is characterized by failure of the pulmonary vasculature in the newborn to adapt after birth, resulting in sustained high pulmonary vascular resistance, abnormal extrapulmonary right-to-left shunting of deoxygenated blood, and refractory hypoxemia. The etiology and pathophysiology of persistent pulmonary hypertension of the newborn may be classified into four broad categories, including maladaptation of a structurally normal cardiopulmonary system, underdevelopment of the lungs, maldevelopment of pulmonary vasculature in the absence of pulmonary parenchymal disease, and intravascular obstructions associated with increased blood viscosity from polycythemia. Infants with persistent pulmonary hypertension of the newborn may present with labile hypoxemia, with or without respiratory distress. Evaluation may include simultaneous pre- and post-ductal oxygen saturation measurements, chest radiography, echocardiography, and arterial blood gas analysis. The hyperoxia test may be useful when echocardiography is unavailable. The main goal in treating persistent pulmonary hypertension of the newborn is to reverse pulmonary vasoconstriction, optimize cardiac function, and improve systemic oxygen delivery. Treatment may include supportive measures such as sedation, correction of metabolic disturbances, management of polycythemia, oxygen therapy, and mechanical ventilation. Targeted therapy, depending on the underlying cause of disease, may include surfactant therapy, pulmonary vasodilator therapy, and optimization of hemodynamic status. Infants with refractory PPHN may require extracorporeal membrane oxygenation. Survivors of moderate to severe disease should be monitored for neurologic abnormalities, hearing loss, and cognitive delay.
Graphical abstract
Highlights
- •
Persistent pulmonary hypertension of the newborn can occur in term or preterm infants.
- •
The pulmonary vasculature fails to adapt after birth, causing refractory hypoxemia.
- •
Causes include maladaptation, underdevelopment, maldevelopment, or obstruction.
- •
Identifying the etiopathophysiology of PPHN is key to guiding therapy.
- •
Sequelae include cardiorespiratory failure, neurodevelopmental delay, and death.
1
Introduction
Persistent pulmonary hypertension of the newborn (PPHN) is a potentially life-threatening condition characterized by failure of the pulmonary vasculature to adapt after birth. This results in sustained high pulmonary vascular resistance, abnormal extrapulmonary right-to-left shunting of deoxygenated blood, and refractory hypoxemia. Severe PPHN is associated with increased risk of cardiorespiratory failure, neurodevelopmental delay, and death. In contrast with the traditional concept that PPHN primarily affects term infants, PPHN is found to be highly prevalent in preterm infants [ ]. The overall incidence of PPHN is 2 per 1000 live births, with a higher incidence in late preterm infants (5.4 per 1000 live births) than in term infants (1.6 per 1000 live births) [ , ]. Early recognition and timely intervention are imperative for improving outcomes in patients who have PPHN.
The purpose of this article is to review the normal and abnormal adaptation of perinatal pulmonary vasculature as well as the etiology, pathophysiology, clinical manifestations, diagnostic methods, and treatment of PPHN.
2
Fetal circulation and pulmonary vascular transition at birth
Fetal circulation begins to develop in the third week of gestation, with a primitive, continuous pulmonary circulation from the right ventricle to left atrium. The number of vessels increases 40-fold from the early canalicular stage to birth, with only a fourfold increase in lung size [ ]. Maturational responses to pulmonary vasodilators, essential for successful transition at birth, occur during the second half of the pregnancy [ ].
Fetal circulation is characterized by sustained high pulmonary vascular resistance that exceeds systemic vascular resistance throughout fetal life. This elevated resistance diverts most of the fetal cardiac output away from the fluid-filled lungs, with only 10 % to 15 % of the cardiac output passing through the fetal pulmonary circulation [ ]. In contrast, the placenta has low resistance to blood flow and functions as the primary organ for gas exchange rather than the fetal lungs. Placental gas exchange occurs between the maternal arteriovenous blood pool and fetal blood [ ]. The oxygenated blood (estimated oxygen saturation, 80 %) enters the umbilical vein and shunts through the ductus venosus, mostly bypassing the liver to join the poorly oxygenated blood (estimated oxygen saturation, ~25 %) from the lower trunk and extremities in the inferior vena cava. Preferential streaming of the oxygenated blood returning from the umbilical vein minimizes mixing with the less oxygenated blood entering the inferior vena cava from the lower fetal body. The oxygenated blood is then shunted through the patent foramen ovale directly into the left atrium (estimated oxygen saturation, 65 %), bypassing the right ventricle and lungs to preferentially supply the fetal brain and heart. The poorly oxygenated blood from the inferior vena cava joins the less oxygenated blood from the superior vena cava at the right atrium (estimated oxygen saturation, 30 %) and flows through the tricuspid valve into the right ventricle, and is ejected into the main pulmonary artery. Due to the high pulmonary vascular resistance of the lungs, only a small fraction of this blood reaches the lungs. Most of this poorly oxygenated blood is diverted through the patent ductus arteriosus into the descending aorta and supplies the lower body before returning to the placenta for reoxygenation.
The elevated fetal pulmonary vascular resistance is sustained by several mechanisms, including mechanical factors such as fluid-filled alveoli and hypoxemia-induced production of vasoconstrictive mediators like endothelin-1, serotonin, and platelet-activating factor, as well as lipid mediators such as thromboxane and leukotrienes [ ]. In addition, low basal availability of vasodilatory agents such as nitric oxide and prostacyclin contributes to the high pulmonary vascular resistance that is observed in the later stages of gestation.
At birth, a selective decrease in pulmonary vascular resistance, combined with an increase in systemic vascular resistance, leads to a significant drop in the pulmonary-to-systemic vascular resistance ratio, which is essential for increasing the pulmonary blood flow for efficient gas exchange and adequate systemic oxygen delivery. This transition begins with the first breath, which inflates the alveoli and increases alveolar oxygen tension. Elevated oxygen tension and physical stimulation result in the production of pulmonary vasodilators, such as prostacyclin and nitric oxide from the endothelium. Nitric oxide acts via the cyclic guanosine monophosphate (cGMP) pathway, and prostacyclin acts via the arachidonic acid and cyclic adenosine monophosphate (cAMP) pathway to cause vasodilation.
The initial marked drop in pulmonary vascular resistance is followed by a series of events that complete the transition from fetal to neonatal circulation. First, pulmonary vascular resistance continues to decrease while pulmonary blood flow increases, driven by elevated levels of shear stress-induced vasodilators and a subsequent reduction in vasoconstriction. Second, clamping of the umbilical cord eliminates the low-resistance placental pathway and increases systemic vascular resistance. Third, the full separation of pulmonary and systemic circulations occurs with the closure of the ductus arteriosus and foramen ovale. These changes enable a progressive increase in pulmonary blood flow, with combined cardiac output increasing from 10 % prenatally to 50 % postnatally [ ]. With successful postnatal transition, the pulmonary-to-systemic vascular resistance ratio decreases from >1 prenatally to <0.2 postnatally [ ]. As a result, the lungs receive as much blood flow as all other organs combined, ensuring proper postnatal adaptation of oxygenation and circulation. The deoxygenated blood that enters the pulmonary vasculature is oxygenated by the lungs and is distributed to the body through systemic circulation. Failure to achieve this postnatal transition to a high flow, low-pressure pulmonary circulation results in PPHN.
3
Etiology and pathophysiology of persistent pulmonary hypertension of the newborn
The pathophysiology of PPHN is complex and may involve multiple etiologies, including perinatal risk factors. At the Sixth World Symposium on Pulmonary Arterial Hypertension in 2019, PPHN was recognized as an entity distinct from pulmonary artery hypertension in pediatric and adult patients because of its timing, reversible course, and response to various therapies [ , ]. The etiology and pathophysiology of PPHN can be classified into four broad categories: maladaptation, underdevelopment, maldevelopment, and intravascular obstruction. Overlap between these categories may occur, ultimately leading to increased pulmonary vascular resistance and decreased pulmonary blood flow. This low-flow, high-pressure system sustains extrapulmonary right-to-left shunting of deoxygenated blood into the systemic circulation through the patent ductus arteriosus and patent foramen ovale, resulting in ventilation-perfusion mismatch and hypoxemia. This fetal circulatory pattern increases right ventricular afterload, causing right ventricular hypertrophy and failure, and decreases venous return and left ventricular output. In patients who have a rigid or protruding septum, decreased left ventricular function may further compromise systemic blood flow, contributing to hypoxemia and acidemia. Hypoxia and acidosis act as potent vasoconstrictors, worsening pulmonary vascular resistance, sustaining a fetal circulatory state, and creating a vicious cycle characteristic of PPHN [ , ]. It is important to identify the individual causes and pathophysiology of PPHN to guide therapy and predict severity and reversibility of the disease.
3.1
Maladaptation
Maladaptation of a structurally normal cardiopulmonary system may cause PPHN. This may be observed in lung parenchymal diseases such as meconium aspiration syndrome, respiratory distress syndrome, congenital pneumonia, and surfactant metabolism dysfunction with an ABCA3 gene mutation. In addition, pulmonary vascular resistance may be increased due to septicemia, hypoxemia, acidemia, and hypothermia. Despite a normal pulmonary vascular structure, these conditions impair vasoreactivity, leading to pulmonary vasoconstriction and PPHN [ ]. Contributing mechanisms may include impaired voltage-gated potassium channels, decreased nitric oxide availability, and increased intracellular calcium in smooth muscle cells. Persistent or recurrent pulmonary vasoconstriction in the newborn may result from the redistribution of blood flow to better ventilated lung areas or acute increase in inflammatory mediators. In contrast to pulmonary artery hypertension and its treatment in older individuals, these conditions in neonates may be transient and respond to therapies specific for PPHN treatment [ ].
3.2
Underdevelopment
Lung hypoplasia is commonly associated with underdeveloped pulmonary circulation. Disruption of lung organogenesis can occur because of restricted fetal breathing or lung compression caused by conditions such as neuromuscular disorders, skeletal dysplasia with thoracic dystrophies, congenital diaphragmatic hernia, and other space-occupying lesions. The most common causes of lung hypoplasia include severe oligohydramnios from preterm prolonged rupture of membranes or renal disorders. In these cases, impaired epithelial homeostasis affects endothelial cell signaling, causing endothelial dysfunction and altered development of the pulmonary vasculature [ ]. This typically results in a decreased number of vessels and increased muscularization of pulmonary arteries and capillaries [ , ].
Genetic factors also may predispose newborns to develop primary pulmonary hypoplasia associated with PPHN. These genetic factors include TBX4 gene (T-box transcription factor 4 gene), which is highly expressed in the lung mesenchyme of the developing fetus, and the genes encoding corticotropin-releasing hormone receptor 1 and corticotropin-releasing hormone binding protein [ ].
3.3
Maldevelopment
In patients with maldevelopment, pulmonary vasculature remodeling may occur in the absence of pulmonary parenchymal disease. This condition is characterized by excessive vascular muscularization, as observed in idiopathic PPHN (10 % to 20 % of patients with PPHN) and chronic fetal hypoxemia. Potential risk factors for antenatal remodeling of the pulmonary vasculature include environmental exposures and genetic variations. Although the evidence is conflicting, maternal exposure to nonsteroidal anti-inflammatory drugs and selective serotonin reuptake inhibitors in the third trimester may induce closure of the fetal ductus arteriosus and cause PPHN [ ]. Alveolar capillary dysplasia is a fatal genetic condition that presents with severe PPHN. This condition is characterized by abnormal development of pulmonary capillaries, misaligned pulmonary veins, and remodeled pulmonary arterioles caused by a mutation in the FOXF1 gene on chromosome 16q24 [ ].
3.4
Intravascular obstructions
Increased blood viscosity due to polycythemia may cause functional intrinsic intravascular obstruction and decreased blood flow to the pulmonary vasculature. Pulmonary vascular resistance may increase exponentially with increasing hematocrit, especially when hematocrit is >54 % [ ].
4
Clinical presentation and diagnosis
During a normal fetal to neonatal transition, as pulmonary artery pressure falls below systemic pressure, most newborns are asymptomatic and achieve pre- and post-ductal oxygen saturation levels >95 % by 24 h. Hence, the recommendation is to perform the critical congenital heart disease screening in newborns no sooner than 24 h of age. While elevated pulmonary arterial pressure in the immediate postnatal period may cause transient clinical signs, such as a loud second heart sound and tricuspid regurgitation murmur, these findings typically subside spontaneously in healthy newborns. Infants who require resuscitation at birth, a pulse oximeter is placed on the right hand or wrist to accurately monitor pre-ductal oxygen saturation (to avoid detection of mixed oxygen saturations) and guide resuscitation. Infants with PPHN, regardless of the etiology, often present with labile hypoxemia that is disproportionate to the degree of lung disease. An oxygen saturation gradient >10 % between the pre-ductal (right arm) and post-ductal measurements (lower extremity) is characteristic of PPHN. These infants may also be hypotensive, lethargic, and exhibit metabolic acidemia. Infants with secondary PPHN caused by maladaptation often present with signs of respiratory distress, such as grunting and retractions. Infants with underdeveloped lungs are usually diagnosed prenatally or shortly after birth and exhibit hypoxemia and respiratory distress resembling secondary PPHN. In contrast, infants with primary or idiopathic PPHN from maldevelopment may show oral cyanosis, tachypnea, and feeding difficulties without any signs of increased work of breathing. PPHN resulting from intravascular obstructions is a rare occurrence and often associated with a concerning prenatal history, such as uncontrolled maternal diabetes, severe intrauterine hypoxemia, or twin-to-twin transfusion syndrome.
Initial evaluation includes a detailed history of risk factors for PPHN, thorough physical examination, and simultaneous pre- and post-ductal oxygen saturation measurements. Chest radiography, echocardiography, and arterial blood gas analysis are essential to confirm the diagnosis of PPHN and identify the cause. Chest radiographs may identify respiratory conditions such as meconium aspiration syndrome, pneumonia, or respiratory distress syndrome. Patients with primary or idiopathic PPHN may have clear lungs with pulmonary vascular oligemia and no infiltrates. Arterial blood gas analysis typically shows severe hypoxemia despite high fractions of inspired oxygen.
The hyperoxia test (arterial partial pressure of oxygen is measured before and after exposure to 100 % oxygen for 10–15 min) may help distinguish PPHN and cardiac disease from lung parenchymal diseases but is seldom performed because of the common availability of echocardiography and potential adverse effects of hyperoxia. In cyanotic heart disease and conditions with a major right-to-left shunt, the arterial oxygen pressure remains <100 mmHg or increases by <20 mmHg despite exposure to hyperoxia. In infants with lung parenchymal disease, arterial oxygen pressure often rises above 100 mmHg or increases by >20 mmHg in response to 100 % oxygen. However, lung parenchymal disease with significant intrapulmonary shunting may not respond with a rise in arterial oxygen pressure above 100 mmHg. Hence, although the hyperoxia test may be useful when echocardiography is unavailable, it should be interpreted with caution, taking clinical presentation and chest radiography into consideration [ ].
Echocardiography is the most reliable non-invasive test for diagnosing PPHN and excluding the presence of structural heart disease. Key echocardiographic findings in patients with PPHN include right ventricular hypertrophy, flattening of the ventricular septum, and right-to-left or bidirectional shunting at the patent ductus arteriosus or patent foramen ovale ( Fig. 1 ). Measuring tricuspid regurgitation jet velocity may help estimate pulmonary artery pressure, which is greater than systemic pressure in PPHN ( Fig. 1 ). The echocardiogram also enables the assessment of left ventricular function, which may be impaired in patients who have PPHN. Serial echocardiograms should be performed to monitor disease progression and treatment response [ , ].
