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Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis

Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis
Authors:
Ann R Stark, MD
Eric C Eichenwald, MD
Section Editor:
Joseph A Garcia-Prats, MD
Deputy Editor:
Laurie Wilkie, MD, MS
Literature review current through: Oct 2022. | This topic last updated: Sep 20, 2022.

INTRODUCTION — Persistent pulmonary hypertension of the newborn (PPHN) occurs when pulmonary vascular resistance (PVR) remains abnormally elevated after birth, resulting in right-to-left shunting of blood through fetal circulatory pathways. This in turn leads to severe hypoxemia that may not respond to conventional respiratory support.

The pathophysiology, clinical features, and diagnosis of PPHN are discussed here. Management and prognosis of PPHN are discussed separately. (See "Persistent pulmonary hypertension of the newborn (PPHN): Management and outcome".)

Related neonatal conditions are discussed in separate topic reviews:

Meconium aspiration syndrome (see "Meconium aspiration syndrome: Pathophysiology, clinical manifestations, and diagnosis")

Neonatal sepsis (see "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates")

Pneumonia (see "Neonatal pneumonia")

Respiratory distress syndrome (see "Clinical features and diagnosis of respiratory distress syndrome in the newborn")

Congenital diaphragmatic hernia (see "Congenital diaphragmatic hernia in the neonate")

Pulmonary hypertension in infants with bronchopulmonary dysplasia (see "Pulmonary hypertension associated with bronchopulmonary dysplasia")

PHYSIOLOGY

Fetal and postnatal circulation – In the fetus, the pulmonary and systemic circuits operate in parallel. Both the right and left ventricles (RV/LV) eject blood into the aorta with subsequent perfusion of the placenta, the fetal organ of respiration (figure 1). The RV is dominant, and blood is shunted right-to-left through the foramen ovale and ductus arteriosus, mostly bypassing the lung, which is not participating in gas exchange.

In contrast, the mature postnatal circulation operates in series. All venous return passes through the right side of the heart and into the lung, where gas exchange occurs. The oxygenated blood returns to the left side of the heart and is pumped into the systemic circulation for oxygen delivery to the tissues. No mixing occurs between the two sides of the circulation.

Transitional circulation – Major circulatory adjustments occur at birth as the organ of gas exchange changes from the placenta to the lung. Under normal circumstances, a progressive fall in pulmonary vascular resistance (PVR) accompanies the immediate rise in systemic vascular resistance (SVR) that occurs after birth. For a short period, a transitional circulatory pattern exists that combines features of both the fetal and adult circulatory patterns. The decline in the PVR/SVR ratio results in a steady increase in pulmonary blood flow and oxygen uptake in the lung.

The process of transition depends upon several factors. Factors that contribute to the postnatal increase in SVR include removal of the placenta, the catecholamine surge associated with birth, and the relatively cold extrauterine environment. Factors that promote the postnatal decrease in PVR include expansion of the lung to normal resting volume, establishment of adequate alveolar ventilation and oxygen tension, and successful clearance of fetal lung fluid.

Conditions that interfere with the normal postnatal decline in the PVR/SVR ratio cause the transitional circulation to persist and result in PPHN.

PATHOGENESIS — Three types of abnormalities of the pulmonary vasculature underlie the disorder: underdevelopment, maldevelopment, and maladaptation [1-5]. Experimental and clinical evidence suggests that injury to the developing pulmonary circulation may disrupt vascular endothelial growth factor (VEGF) signaling and contribute to these abnormalities [6].

Underdevelopment of the pulmonary vasculature – In abnormalities of underdevelopment, the cross-sectional area of the pulmonary vasculature is reduced, resulting in a relatively fixed elevation of pulmonary vascular resistance (PVR). Mortality risk is greatest in this category of patients, as adaptive postnatal pulmonary vasodilation is limited. Underdevelopment occurs with pulmonary hypoplasia associated with a variety of conditions. These include congenital diaphragmatic hernia (CDH), congenital pulmonary (cystic adenomatoid) malformation, renal agenesis, oligohydramnios accompanying obstructive uropathy, and fetal growth restriction. (See "Congenital diaphragmatic hernia in the neonate" and "Congenital pulmonary airway malformation" and "Renal agenesis: Prenatal diagnosis" and "Overview of congenital anomalies of the kidney and urinary tract (CAKUT)" and "Renal hypodysplasia" and "Infants with fetal (intrauterine) growth restriction".)

Maldevelopment of the pulmonary vasculature – Maldevelopment is a perturbation that occurs in lungs that are otherwise structurally normal (ie, normal number of pulmonary vessels, normal branching, normal alveolar differentiation). The characteristics of maldeveloped pulmonary vasculature include abnormal thickening of the muscle layer of the pulmonary arterioles, and extension of this layer into small vessels that normally have thin walls and no muscle cells [4]. The extracellular matrix that surrounds the pulmonary vessels also is excessive. In this disorder, remodeling of the pulmonary vascular bed is thought to occur during the first 7 to 14 days after birth, with an accompanying fall in PVR.

Conditions associated with PPHN caused by vascular maldevelopment include postterm delivery, meconium staining, and meconium aspiration syndrome (MAS). In these disorders, the pulmonary vasculature responds poorly to interventions that usually are effective at reducing PVR (eg, supplemental oxygen, mechanical ventilation). (See "Meconium aspiration syndrome: Pathophysiology, clinical manifestations, and diagnosis".)

Disorders that cause pulmonary overcirculation during fetal development also may predispose to vascular maldevelopment. These causes include premature closure of the ductus arteriosus (eg, caused by nonsteroidal anti-inflammatory drugs [NSAIDs]) or foramen ovale, high placental vascular resistance, and total anomalous pulmonary venous drainage. It has been proposed that the use of NSAIDs in pregnancy is associated with PPHN due to ductal constriction in the fetus [7]. However, subsequent data are conflicting on whether there is a true association between maternal use of NSAIDs and PPHN [8,9]. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'NSAIDs'.)

The mechanisms that stimulate maldevelopment of the pulmonary vasculature are uncertain, but vascular mediators appear to play a role. In one report, for example, infants with severe PPHN had, compared with healthy controls, higher plasma concentrations of the vasoconstrictor endothelin-1 and lower concentrations of cyclic guanosine monophosphate (representing stimulation of guanylate cyclase by nitric oxide [NO], a vasodilator that cannot be readily measured) [10].

Genetic predisposition may influence the availability of precursors for NO synthesis and affect cardiopulmonary adaptation at birth. This was illustrated in a report in which infants with pulmonary hypertension (PH) had lower plasma concentrations of arginine, a precursor of NO and a urea cycle intermediate, and NO metabolites than control infants with respiratory distress [11]. A functional polymorphism of the gene encoding carbamoyl-phosphate synthetase, which controls the rate-limiting step in the urea cycle, occurred more frequently in all of the infants with respiratory distress, with or without PH, than in the general population.

Maladaptation of the pulmonary vasculature – In maladaptation, the pulmonary vascular bed is normally developed. However, adverse perinatal conditions cause active vasoconstriction and interfere with the normal postnatal fall in PVR. These conditions include perinatal depression, pulmonary parenchymal diseases, and bacterial infections, especially those caused by group B streptococcus (GBS). The mechanism of increased PVR with GBS infection is activation of vasoactive mediators by bacterial phospholipid components. In a study in newborn lambs, PH was induced by infusion of cardiolipin and phosphatidylglycerol, phospholipids located primarily in the cell wall of GBS [12]. (See "Group B streptococcal infection in neonates and young infants", section on 'Pneumonia'.)

EPIDEMIOLOGY — The prevalence of PPHN has been estimated at approximately 2 cases per 1000 live births [13,14]. PPHN usually occurs in term and late preterm infants, although it may also present postterm infants [13]. PPHN is rare in very low birth weight (VLBW) infants (BW <1500 g) [15]; however, data from a retrospective multicenter study suggest that the prevalence of PPHN has increased in extremely preterm infants (gestational age [GA] <28 weeks) and the risk increases with decreasing GA [16].

Reported maternal and prenatal risk factors for PPHN include [13,14]:

Maternal diabetes (gestational or preexisting diabetes) (see "Infants of women with diabetes", section on 'Neonatal effects')

Maternal obesity (see "Obesity in pregnancy: Complications and maternal management", section on 'Offspring')

Advanced maternal age (see "Effects of advanced maternal age on pregnancy")

In utero exposure of selective serotonin reuptake inhibitors (SSRIs) (see "Antenatal exposure to selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs): Neonatal outcomes", section on 'Persistent pulmonary hypertension of the newborn')

Black race

Meconium stained amnionic fluid (see "Meconium aspiration syndrome: Pathophysiology, clinical manifestations, and diagnosis")

Large or small for gestational age (see "Large for gestational age newborn" and "Infants with fetal (intrauterine) growth restriction")

Prolonged premature rupture of the membranes appears to be a risk factor among preterm infants [15]

CLINICAL MANIFESTATIONS

Neonatal findings — Most neonates with PPHN present within the first 24 hours of life with signs of respiratory distress (eg, tachypnea, retractions, and grunting) and cyanosis. In one study, more than half of the infants had low apgar scores and almost all of the patients received delivery room interventions including oxygen therapy, bag and mask ventilation, and endotracheal intubation [13].

Physical examination findings include cyanosis and signs of respiratory distress. In addition, there may be meconium staining of skin and nails, which may be indicative of intrauterine stress. The cardiac examination of infants with PPHN may be notable for a prominent precordial impulse, and a narrowly split and accentuated second heart sound. A harsh systolic murmur consistent with tricuspid insufficiency sometimes is heard at the lower left sternal border.

Associated conditions — Most infants with PPHN have associated respiratory or systemic conditions. The relative frequencies of these associated conditions are as follows [13,14]:

Meconium aspiration syndrome (MAS, 25 to 40 percent) (see "Meconium aspiration syndrome: Pathophysiology, clinical manifestations, and diagnosis")

Sepsis (20 to 30 percent) (see "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates")

Pneumonia (15 to 20 percent) (see "Neonatal pneumonia")

Respiratory distress syndrome (10 to 15 percent) (see "Clinical features and diagnosis of respiratory distress syndrome in the newborn")

Congenital diaphragmatic hernia (CDH, approximately 5 to 10 percent) (see "Congenital diaphragmatic hernia in the neonate")

Other pulmonary conditions (approximately 4 to 5 percent)

Perinatal asphyxia (1 to 2 percent) (see "Perinatal asphyxia in term and late preterm infants")

Idiopathic (no other condition observed, 15 to 20 percent)

Initial evaluation — Most patients undergo initial testing that includes pulse oximetry, arterial blood gas sampling, chest radiography, and sepsis evaluation. However, the diagnosis is generally made by echocardiography. (See 'Diagnosis' below.)

Pre- and postductal oxygen saturation — Pulse oximetry assessment generally demonstrates a difference of >10 percent between the pre- and postductal (right thumb and either great toe) oxygen saturation. This differential is due to right-to-left shunting through the patent ductus arteriosus (PDA). However, it is important to recognize that the absence of a pre- and postductal gradient in oxygenation does not exclude the diagnosis of PPHN, since right-to-left shunting can occur predominantly through the foramen ovale rather than the PDA.

Arterial blood gas — An arterial blood gas sample typically will show low arterial partial pressure of oxygen (PaO2 <100 mmHg in patients receiving 100 percent inspired oxygen concentration), particularly samples that are postductal. However, in contrast to infants with cyanotic cardiac lesions, many infants with PPHN have at least one measurement of PaO2 >100 mmHg early in the course of their illness. The arterial partial pressure of carbon dioxide (PaCO2) is normal in infants without accompanying lung disease. The right-to-left shunting of blood through the PDA can also be documented in differences in PaO2 between samples obtained from the right radial artery (preductal sample) and the umbilical artery (postductal sample). (See "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn", section on 'Measurement of oxygenation'.)

Chest radiograph — The chest radiograph may be normal, or it may demonstrate findings of an associated pulmonary condition (eg, pneumonia, meconium aspiration, or CDH). The heart size typically is normal or slightly enlarged. Pulmonary blood flow may appear normal or reduced.

Sepsis evaluation — Since sepsis is a common cause of PPHN, neonates presenting with cyanosis and respiratory distress should undergo sepsis evaluation and should receive empiric antibiotics pending culture results. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Evaluation and initial management'.)

DIAGNOSIS

Echocardiography — The definitive diagnosis of PPHN is made by echocardiography. Echocardiography is an essential test in any infant with unremitting cyanosis that is unexplained by parenchymal lung disease, to exclude structural heart disease and confirm a diagnosis of PPHN.

In PPHN, echocardiography demonstrates normal structural cardiac anatomy with evidence of pulmonary hypertension (PH) (ie, elevated right ventricle pressure [RVp]). Echocardiography also assesses ventricular function, which may be impaired.

RVp can be estimated based upon Doppler measurement of the velocity of the tricuspid regurgitation (TR) jet, if present [5]. If there is no TR, RVp can be assessed qualitatively (eg, flattened or displaced ventricular septum). In patients with severe PH (systemic or suprasystemic RVp), echocardiography may demonstrate right-to-left shunting through the patent ductus arteriosus and/or foramen ovale. (See "Echocardiographic assessment of the right heart", section on 'Estimation of pulmonary artery systolic pressure'.)

Severity of PH — Echocardiography also provides an estimation of the severity of the PH and the degree of ventricular dysfunction.

The estimated RVp, using assessments of TR jet and/or changes in septal position, is compared with systemic blood pressure (BP) to determine the severity of PH as follows:

Mild to moderate PPHN – Estimated RVp is between one-half to three-quarters systemic BP

Moderate to severe PPHN – Estimated RVp is greater than three-quarters systemic BP but less than systemic BP

Severe PPHN – Estimated RVp greater than systemic BP

Evidence of RV dysfunction suggests severe PH

Evidence of biventricular dysfunction may represent global insult (eg, perinatal depression)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of PPHN includes:

Cyanotic congenital heart disease (CHD) (table 1), which is distinguished from PPHN by echocardiography. (See "Cardiac causes of cyanosis in the newborn" and "Diagnosis and initial management of cyanotic heart disease in the newborn".)

Primary isolated parenchymal lung disease such as neonatal pneumonia, meconium aspiration syndrome, transient tachypnea of the newborn (TTN), and respiratory distress syndrome (RDS). These disorders are usually differentiated from PPHN by the clinical setting and chest radiography. However, as noted above, most patients with PPHN will also have an associated lung disorder. In these patients, echocardiography confirms the diagnosis of PPHN. (See "Overview of neonatal respiratory distress and disorders of transition", section on 'Clinical features' and "Overview of neonatal respiratory distress and disorders of transition", section on 'Chest imaging'.)

Sepsis is distinguished by the clinical setting, positive blood cultures, and echocardiography. However, PPHN may occur as a consequence of sepsis. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Clinical manifestations'.)

Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD-MPV) is a rare disorder that may have a similar presentation to severe PPHN (ie, severe hypoxia that is refractory to general supportive care). However, infants with ACD-MPV typically have an initial period of stability and develop severe hypoxemia later than PPHN after the first few hours or days of life. If a diagnosis of ACD-MPV is suspected further evaluation including catheterization and lung biopsy are needed to confirm the diagnosis. (See "Classification of diffuse lung disease (interstitial lung disease) in infants and children", section on 'Alveolar capillary dysplasia with or without misalignment of the pulmonary veins' and "Approach to the infant and child with diffuse lung disease (interstitial lung disease)", section on 'Diagnostic approach'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pulmonary hypertension in children".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Persistent pulmonary hypertension in a newborn (The Basics)")

SUMMARY AND RECOMMENDATIONS

Pathophysiology – Persistent pulmonary hypertension of the newborn (PPHN) occurs when pulmonary vascular resistance (PVR) remains abnormally elevated after birth, resulting in right-to-left shunting of blood through fetal circulatory pathways (figure 1); this leads to hypoxemia, which may be severe. (See 'Physiology' above.)

Associated conditions – PPHN is usually associated with an underlying respiratory or systemic condition, though 15 to 20 percent of cases are idiopathic. Associated conditions include (see 'Associated conditions' above):

Meconium aspiration syndrome (MAS) (see "Meconium aspiration syndrome: Pathophysiology, clinical manifestations, and diagnosis")

Sepsis (see "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates")

Pneumonia (see "Neonatal pneumonia")

Respiratory distress syndrome (RDS) (see "Clinical features and diagnosis of respiratory distress syndrome in the newborn")

Congenital diaphragmatic hernia (CDH) (see "Congenital diaphragmatic hernia in the neonate")

Other pulmonary conditions

Perinatal asphyxia (see "Perinatal asphyxia in term and late preterm infants")

Clinical manifestations – Neonates with PPHN typically present within the first 24 hours of life with signs of respiratory distress (eg, tachypnea, retractions, and grunting) and cyanosis. (See 'Clinical manifestations' above.)

Evaluation and diagnosis – Initial testing includes pulse oximetry, arterial blood gas sampling, chest radiography, and sepsis evaluation. Diagnosis of PPHN is confirmed by echocardiogram, which shows normal cardiac anatomy with evidence of pulmonary hypertension ([PH]; ie, flattened or displaced ventricular septum, elevated right ventricular pressure [RVp]). (See 'Initial evaluation' above and 'Diagnosis' above.)

Differential diagnosis – The differential diagnosis of PPHN includes cyanotic congenital heart disease (CHD) (table 1), primary pulmonary disorders (eg, MAS, pneumonia, transient tachypnea of the newborn, RDS, CDH, alveolar capillary dysplasia), and sepsis. (See 'Differential diagnosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges James Adams, Jr., MD, who contributed to an earlier version of this topic review.

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