INTRODUCTION — Respiratory distress is common immediately after birth, and is typically caused by abnormal respiratory function during the transition from fetal to neonatal life. It is manifested by tachypnea, nasal flaring, intercostal or subcostal retractions, audible grunting, and cyanosis. Neonatal respiratory distress may be transient; however, persistent distress requires a rational diagnostic and therapeutic approach to optimize outcome and minimize morbidity.

This topic review provides an overview of the pathogenesis, clinical features, and approach to initial management of three common respiratory disorders of perinatal transition: transient tachypnea of the newborn (TTN), respiratory distress syndrome (RDS), and persistent pulmonary hypertension of the newborn (PPHN). These disorders, including their specific management, are discussed in greater detail separately. (See "Pathophysiology, clinical manifestations, and diagnosis of respiratory distress syndrome in the newborn" and "Persistent pulmonary hypertension of the newborn" and "Transient tachypnea of the newborn".)

TRANSITION FROM FETAL LIFE — The successful transition from fetal to neonatal life at delivery requires a series of rapid physiologic changes of the cardiorespiratory system. These changes result in redirection of gas exchange from the placenta to the lung, and comprise:

●Replacement of alveolar fluid with air [1]

●Onset of regular breathing

●Increase in pulmonary blood flow as a result of increased systemic vascular resistance and decreased pulmonary vascular resistance (PVR)

These processes result in an increase in neonatal arterial oxygen tension (PaO₂) from 25 to a range of 60 to 80 mmHg during the first minutes of life. This increase in PaO₂ reverses hypoxic respiratory depression and contributes to a regular breathing pattern [2].

Although most neonates successfully transition between intrauterine and extrauterine life, approximately 10 percent will have difficulty and require resuscitative efforts at birth. This difficulty may be a consequence of impaired lung function due to fluid retention, airway obstruction associated with congenital anomalies, persistent pulmonary hypertension, or apnea associated with lack of respiratory effort. (See "Neonatal resuscitation in the delivery room" and "Persistent pulmonary hypertension of the newborn" and "Management of apnea of prematurity".)

Physiologic transition from intrauterine to extrauterine life, including its difficulties, is discussed in detail separately. (See "Physiologic transition from intrauterine to extrauterine life".)

PATHOGENESIS — The pathogenesis of the common causes of neonatal respiratory distress is reviewed briefly here. A more detailed discussion for each disorder is found separately.

Transient tachypnea of the newborn (TTN) — TTN is caused by failure of adequate lung fluid clearance at birth, resulting in excess lung liquid. The liquid fills the air spaces and moves into the extra-alveolar interstitium, where it pools in perivascular tissues and interlobar fissures until it is cleared by the lymphatic or vascular circulation. (See "Transient tachypnea of the newborn".)

Although the precise pathogenesis of TTN remains unknown, it is proposed that TTN is caused by impairment of the following mechanisms that normally clear fetal alveolar fluid:

●Activation of amiloride-sensitive sodium channels, which increases sodium reabsorption, thereby creating an osmotic gradient for water uptake across the pulmonary epithelium [3]. The ability to reabsorb sodium appears relatively late in fetal life. Low pulmonary expression or activity of airway epithelial sodium channels may delay lung fluid clearance, especially in preterm infants [4].

●Lung inflation that generates a transepithelial hydrostatic pressure gradient, which promotes fluid movement of liquid from the airway. This is consistent with the finding that positive end-expiratory pressure (PEEP) facilitates airway liquid clearance and lung aeration in animal models mechanically ventilated from birth [5].

The excess lung water in TTN causes decreased pulmonary compliance, and possibly increased airway resistance due to extrinsic compression of small airways by fluid in the extra-alveolar interstitium.

Respiratory distress syndrome (RDS) — RDS is caused by deficiency of surfactant, the phospholipid mixture (predominantly desaturated palmitoyl phosphatidyl choline) that reduces alveolar surface tension, which decreases the pressure needed to keep the alveoli inflated, and maintains alveolar stability. When surfactant is deficient, the infant may not be able to generate the increased inspiratory pressure needed to inflate alveolar units, resulting in the development of progressive and diffuse atelectasis. Surfactant deficiency also leads to an inability to maintain open alveoli at low lung volume, for example, during end expiration [6].

Diffuse atelectasis leads to low compliance and low functional residual capacity. Hypoxemia results primarily from mismatching of ventilation and perfusion as blood bypasses atelectatic air spaces (intrapulmonary shunting). Right-to-left shunting that occurs through the ductus arteriosus and foramen ovale, because of increased pulmonary vascular resistance (PVR), also contributes to decreased oxygenation. Hypoxemia is often accompanied by respiratory and/or metabolic acidosis. (See "Pathophysiology, clinical manifestations, and diagnosis of respiratory distress syndrome in the newborn".)

Although surfactant deficiency plays the major etiologic role for neonatal RDS, the inability to clear lung fluid from air spaces may also contribute to RDS in the preterm infant [4]. In addition, data from a twin cohort study demonstrate a significant genetic susceptibility to RDS, although the underlying genetic component(s) remains to be elucidated [7].

Persistent pulmonary hypertension (PPHN) — PPHN is caused by the abnormal persistence of elevated PVR that leads to right-to-left shunting of deoxygenated blood through the foramen ovale and the ductus arteriosus, resulting in hypoxemia.

The normal transition from fetal life must include a dramatic decrease in PVR. This is mediated by mechanical factors that result in the opening of air spaces and improved oxygenation, and decrease pulmonary vasoconstriction. The balance of vascular mediators (ie, endothelin and nitric oxide, which induce vasoconstriction and vasorelaxation, respectively) also plays a key role in changing pulmonary vascular tone.

It has been proposed that PPHN is caused by a combination of underdevelopment, maldevelopment, or maladaptation of the pulmonary vascular bed. PPHN is also often associated with nonacute conditions due to a structural abnormality (eg, congenital diaphragmatic hernia) or chronic in utero stress (eg, meconium aspiration syndrome). These concurrent findings suggest that a structural etiology (eg, increased musculature of pulmonary vessels), rather than simply a functional change in pulmonary vascular reactivity at birth, contributes to PPHN in many cases. (See "Persistent pulmonary hypertension of the newborn", section on 'Pathogenesis'.)

CLINICAL FEATURES — Characteristic clinical features help distinguish among the disorders that result in respiratory distress immediately after birth, although there can be considerable overlap among these conditions.

Transient tachypnea of the newborn (TTN) — TTN is most frequently seen in late preterm infants born at a gestational age between 34 and 37 weeks, many of whom are delivered by elective caesarean section [8]. Term and postterm babies are also at risk for TTN.

The onset of TTN usually occurs within two hours after delivery. Tachypnea (respiratory rate ≥60 breaths per minute) is the most prominent feature. Affected infants also may have increased work of breathing manifested by nasal flaring, mild intercostal and subcostal retractions, and expiratory grunting (the sound produced by expiration through partially closed vocal cords). These signs of respiratory distress are generally mild and often resolve more quickly than tachypnea. Cyanosis may be present and is usually corrected with low concentrations of supplemental oxygen. Respiratory acidosis, if present, is mild. While TTN frequently resolves within 24 hours, a persistent course of up to 72 hours is not uncommon. (See "Transient tachypnea of the newborn".)

Respiratory distress syndrome (RDS) — Infants with RDS are nearly always preterm. Respiratory distress (ie, tachypnea and labored breathing) and cyanosis occur at or soon after birth. Typical signs include grunting (which prevents end-expiratory alveolar collapse), nasal flaring (which reduces nasal resistance and reflects increased use of accessory muscles of respiration), and intercostal and subcostal retractions (due to decreased lung compliance and the highly compliant chest wall). (See "Pathophysiology, clinical manifestations, and diagnosis of respiratory distress syndrome in the newborn".)

The characteristic clinical course of RDS is observed less frequently because of interventions that reduce the risk of RDS. These include the use of antenatal glucocorticoid therapy, early intubation for surfactant therapy, and/or administration of continuous positive air pressure (CPAP) or positive end-expiratory pressure (PEEP) in the delivery room to provide adequate lung volume [9]. As a result of these measures, many extremely low birth weight (ELBW; BW <1000 g) infants do not exhibit the clinical features of RDS, even though they are at considerable risk for later development of bronchopulmonary dysplasia (BPD). (See "Pathophysiology, clinical manifestations, and diagnosis of respiratory distress syndrome in the newborn" and "Bronchopulmonary dysplasia: Definition, pathogenesis, and clinical features".)

Persistent pulmonary hypertension (PPHN) — PPHN usually occurs in term infants, although it may also present in late preterm or postterm infants. Although the diagnosis is rare in very low birth weight (VLBW; BW <1500 g) infants, PPHN may dominate the clinical picture of respiratory distress in a small number of VLBW infants.

PPHN is characterized by tachypnea and cyanosis. Differential pre- and postductal saturation is a common finding (see 'Cardiac evaluation' below). It may also be accompanied by a systolic murmur of tricuspid insufficiency. Sepsis, hypoxia-ischemia, meconium aspiration syndrome, and congenital diaphragmatic hernia are associated with PPHN. In these cases, metabolic acidosis may be present due to lactic acidosis from poor perfusion or severe hypoxemia, in addition to the respiratory acidosis that accompanies respiratory failure. (See "Persistent pulmonary hypertension of the newborn".)

Other etiologies — Other disorders that can result in neonatal respiratory distress include:

●Pneumonia (see "Neonatal pneumonia", section on 'Clinical presentation')

●Congenital heart disease (see "Cardiac causes of cyanosis in the newborn", section on 'Cardiac causes of cyanosis')

●Pneumothorax and other pulmonary air leak disorders (see "Pulmonary air leak in the newborn")

●Congenital diaphragmatic hernia (see "Congenital diaphragmatic hernia in the neonate", section on 'Clinical manifestations')

●Rare pulmonary congenital defects include:

•Tracheoesophageal fistula (see "Congenital anomalies of the intrathoracic airways and tracheoesophageal fistula")

•Cystic adenomatous malformation (see "Congenital pulmonary airway malformation")

•Primary ciliary dyskinesia [10] (see "Primary ciliary dyskinesia (immotile-cilia syndrome)")

DIAGNOSIS — The initial clinical diagnosis of newborns with respiratory distress is based primarily upon the history and radiographic findings, as the physical findings are often similar among the different pulmonary conditions. The evolving course also helps define the specific disorder.

History — Information about the gestational age, method of delivery, risk of infection, and associated complications will assist in the diagnosis, as demonstrated by the following:

●Transient tachypnea of the newborn (TTN) is a frequent cause of respiratory distress in the late preterm infant after caesarean delivery without labor, because of the failure to initiate the normal physiologic mechanisms that contribute to lung fluid clearance. (See 'Transient tachypnea of the newborn (TTN)' above.)

●Preterm infants are at increased risk of respiratory distress syndrome (RDS), and the risk rises as gestational age decreases. In addition, RDS occurs more frequently in infants of diabetic mothers compared with infants of nondiabetic mothers at similar gestational age. (See "Pathophysiology, clinical manifestations, and diagnosis of respiratory distress syndrome in the newborn" and "Infants of women with diabetes".)

●Infants born through meconium-stained amniotic fluid and those who have perinatal depression are at increased risk for persistent pulmonary hypertension (PPHN). PPHN also is more likely in infants with a history of bacterial infection, poor intrauterine growth, and nonreassuring fetal heart rate patterns, suggesting poor placental function and chronic fetal hypoxemia. Although the presence of respiratory distress and precipitating factor(s) are clinical findings that help distinguish PPHN from structural cyanotic heart disease in term infants with severe cyanosis, the diagnosis should be confirmed by echocardiography. (See 'Cardiac evaluation' below and "Persistent pulmonary hypertension of the newborn", section on 'Diagnosis'.)

Chest radiography — Chest radiographic findings may be useful in differentiating among the disorders of neonatal respiratory distress:

●The chest radiograph in TTN usually exhibits characteristic bilateral perihilar linear streaking secondary to engorged lymphatic or blood vessels. Patchy infiltrates that clear within 24 to 48 hours may also reflect the fluid retention of TTN, but make initial differentiation from pneumonia problematic. Lung ultrasound has been proposed as an imaging technique for reliable early diagnosis and differentiation of TTN (image 1) [11].

●In RDS, atelectasis results in the classical radiographic findings of a diffuse, reticulogranular, ground glass appearance with air bronchograms, and low lung volume (image 2).

●The appearance of the chest radiograph in PPHN depends upon the presence of associated lung disease. In infants without lung disease, the lung fields may appear clear with decreased pulmonary vascularity. The heart size may be normal or increased.

Other imaging modalities — Neonatal chest ultrasonography has been proposed to differentiate RDS from transient tachypnea of the newborn, and to predict noninvasive (continuous positive airway pressure [CPAP]) ventilation failure [12].

Cardiac evaluation — Echocardiography should be performed in infants with severe hypoxemia to exclude structural heart disease. In particular, because of the possible paucity of chest radiographic findings in infants with PPHN, echocardiography is an important diagnostic tool to differentiate this disorder from cyanotic heart disease.

In infants with PPHN, echocardiography will show a structurally normal heart with signs of elevated right ventricular pressure and right-to-left shunting through the foramen ovale and/or the ductus arteriosus. In the presence of atrial right-to-left shunting, there will be poor oxygenation measured in all extremities. If right-to-left shunting is limited to the ductus, simultaneous measurements of oxygenation will reveal lower levels in the postductally perfused regions.

MANAGEMENT

Initial management — Our initial approach to an infant with respiratory distress (respiratory rate >60 breaths per minute), regardless of etiology, consists of the following:

●Use mask continuous positive airway pressure (CPAP), and if needed, low supplemental oxygen to relieve respiratory distress or cyanosis. For ongoing management of preterm infants with respiratory distress, oxygenation saturation based upon pulse oximetry (SpO₂) is typically targeted between 90 and 95 percent; however, the optimal SpO₂ range for infants based upon gestational age remains an area of investigation [9]. If persistent pulmonary hypertension (PPHN) is suspected, targeted oxygen saturation should be kept at or above the high end of this range. Noninvasive measurement of oxygenation should be complemented by a blood gas to evaluate presence of respiratory or metabolic acidosis. (See "Neonatal target oxygen levels for preterm infants", section on 'Oxygen target levels'.)

●Assisted ventilation via CPAP, or intubation with mechanical ventilation, may be needed for infants with respiratory failure. (See "Overview of mechanical ventilation in neonates".)

●As discussed above, a chest radiograph should be obtained to assist in diagnosis and to identify complications, such as pneumothorax, that may require urgent treatment. (See "Pulmonary air leak in the newborn".)

●Appropriate fluid and metabolic management and provision of a neutral thermal environment reduce the infant's energy and oxygen consumption. (See "Fluid and electrolyte therapy in newborns".)

●In the majority of infants, initial laboratory evaluation includes a blood gas, and complete blood count and blood culture. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants", section on 'Laboratory tests'.)

●Empiric antibiotics, typically ampicillin and gentamicin, should be considered if there is delayed transitioning or progressive respiratory distress, or if sepsis risk factors are present. The results of blood culture, chest radiography, and clinical course will guide the duration of antibiotic therapy. The dosing regimen of antibiotics is dependent upon the gestational age of the infant. (See "Management and outcome of sepsis in term and late preterm infants".)

Specific therapy — Specific therapy for the three main causes of neonatal respiratory distress is discussed separately.

●Transient tachypnea of the newborn (TTN) (see "Transient tachypnea of the newborn", section on 'Management')

●The prevention and management of an infant with respiratory distress syndrome (RDS) (see "Prevention and treatment of respiratory distress syndrome in preterm infants")

●Persistent pulmonary hypertension (PPHN) (see "Persistent pulmonary hypertension of the newborn", section on 'Management')

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 5^th to 6^th 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 10^th to 12^th 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: Transient tachypnea of the newborn (The Basics)")

SUMMARY AND RECOMMENDATIONS — Respiratory distress is common immediately after birth. Clinical findings include tachypnea, nasal flaring, intercostal or subcostal retractions, audible grunting, and cyanosis.

●Neonatal respiratory distress commonly occurs because of a poor transition from fetal to neonatal life due to impaired lung function, persistent pulmonary hypertension, airway obstruction, or lack of respiratory effort. (See 'Transition from fetal life' above.)

●The three most common causes of respiratory distress are transient tachypnea of the newborn (TTN), respiratory distress syndrome (RDS), and persistent pulmonary hypertension of the newborn (PPHN). Clinical and radiographic findings, and disease course are used to differentiate the three and make an initial diagnosis. (See 'Pathogenesis' above and 'Clinical features' above and 'Diagnosis' above.)

•TTN is typically seen in late preterm infants, although term and postterm infants are also at risk. It is caused by inadequate lung fluid clearance at birth that results in excess lung fluid, which leads to decreased pulmonary compliance and possibly increased airway resistance. TTN is characterized by the onset of tachypnea usually within two hours after delivery. Symptoms generally resolve after 12 to 24 hours, but may persist as long as 72 hours in severe cases. The chest radiograph typically exhibits bilateral perihilar linear streaking. (See "Transient tachypnea of the newborn".)

•RDS typically occurs in preterm infants, and its incidence increases with decreasing gestational age. It is caused by surfactant deficiency that leads to alveolar collapse and diffuse atelectasis. Hypoxemia results from the mismatch of ventilation and perfusion as blood bypasses the atelectatic air spaces. Respiratory distress and cyanosis occur at or soon after birth. The chest radiograph is characterized by low lung volumes and the classical findings of a diffuse, reticulogranular, ground glass appearance with air bronchograms (image 2). (See "Pathophysiology, clinical manifestations, and diagnosis of respiratory distress syndrome in the newborn".)

•PPHN usually occurs in term infants, although it may also present in late preterm or postterm infants. It is caused by the abnormal persistence of elevated pulmonary vascular resistance (PVR) that leads to right-to-left shunting of deoxygenated blood through the foramen ovale and the ductus arteriosus, resulting in hypoxemia. PPHN is characterized by severe cyanosis and tachypnea, and may be accompanied by a systolic murmur of tricuspid insufficiency. The appearance of the chest radiograph in PPHN depends upon the presence of associated lung disease. In infants without lung disease, the lung fields may appear clear with decreased pulmonary vascularity, and the heart size may be normal or increased. Echocardiography is required to confirm the diagnosis of PPHN and differentiate it from structural cyanotic heart disease. (See "Persistent pulmonary hypertension of the newborn".)

●We suggest the following initial management of neonatal respiratory distress regardless of the etiology (Grade 2C):

•Supplemental oxygen for respiratory distress or cyanosis.

•Assisted ventilation via continuous positive airway pressure (CPAP) or intubation in infants with respiratory failure.

•Diagnostic chest radiography.

•Fluid and electrolyte management and a neutral thermal environment to minimize energy and oxygen consumption.

•Laboratory evaluation, including blood gas, complete blood count, and blood culture.

•Empiric antibiotic therapy of ampicillin and gentamicin should be considered if there is delayed transitioning or progressive respiratory distress, or if sepsis risk factors are present.

●Specific therapy for TTN, RDS, and PPHN is discussed separately. (See "Transient tachypnea of the newborn", section on 'Management' and "Prevention and treatment of respiratory distress syndrome in preterm infants" and "Persistent pulmonary hypertension of the newborn", section on 'Management'.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Stephen E Welty, MD, and Firas Saker, MD, FAAP, who contributed to an earlier version of this topic review.