Overview of neonatal respiratory distress and disorders of transition

INTRODUCTION — Respiratory distress immediately after birth is common 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 will provide a broad overview of the pathogenesis and clinical features of three common respiratory disorders of perinatal transition, which are discussed is greater detail separately:

●Transient tachypnea of the newborn (TTN) (see "Transient tachypnea of the newborn")

●Respiratory distress syndrome (RDS) (see "Respiratory distress syndrome (RDS) in the newborn: Clinical features and diagnosis" and "Respiratory distress syndrome (RDS) in preterm infants: Management")

●Persistent pulmonary hypertension of the newborn (PPHN). These disorders, including their specific management, are discussed in greater detail separately. (See "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis" and "Persistent pulmonary hypertension of the newborn (PPHN): Management and outcome".)

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 (PPHN): Clinical features and diagnosis" 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".)

ETIOLOGY AND PATHOGENESIS — Common causes of neonatal respiratory distress are briefly summarized 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 "Respiratory distress syndrome (RDS) in the newborn: Clinical features and diagnosis".)

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 (PPHN): Clinical features and diagnosis", section on 'Pathogenesis'.)

Other etiologies — Other causes of neonatal respiratory distress include:

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

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

●Congenital heart disease (see "Identifying newborns with critical congenital heart disease" and "Diagnosis and initial management of cyanotic heart disease in the newborn")

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

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

●Neonatal abstinence syndrome (see "Prenatal substance exposure and neonatal abstinence syndrome (NAS): Management and outcomes")

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

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

●Congenital pulmonary airway malformation (see "Congenital pulmonary airway malformation")

●Other rare congenital primary pulmonary disorders, including (see "Classification of diffuse lung disease (interstitial lung disease) in infants and children", section on 'Disorders more prevalent in infancy'):

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

•Genetic surfactant disorders (see "Genetic disorders of surfactant dysfunction")

•Inherited pulmonary alveolar proteinosis (see "Pulmonary alveolar proteinosis in children")

•Alveolar capillary dysplasia (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')

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 "Respiratory distress syndrome (RDS) in the newborn: Clinical features and diagnosis", section on 'Clinical manifestations'.)

Because many centers routinely initiate positive pressure respiratory support shortly after birth in preterm neonates born at <32 weeks gestation, the characteristic clinical features of RDS (ie, respiratory distress and cyanosis) may not be apparent. (See "Respiratory distress syndrome (RDS) in preterm infants: Management", section on 'Initial management'.)

Persistent pulmonary hypertension (PPHN) — PPHN usually affects term infants, although it can occur in late preterm or postterm infants. PPHN is usually associated with an underlying respiratory or systemic condition (eg, meconium aspiration, sepsis, pneumonia, perinatal asphyxia, congenital diaphragmatic hernia) though 15 to 20 percent of cases are idiopathic. (See "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis", section on 'Associated conditions'.)

Neonates with PPHN typically present within the first 24 hours after birth with signs of respiratory distress (eg, tachypnea, retractions, and grunting) and cyanosis. Differential pre- and postductal oxygen saturation is a common finding. (See "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis".)

DIAGNOSTIC APPROACH — Diagnostic evaluation is appropriate for neonates who have significant respiratory distress and/or hypoxemia. Diagnostic testing may not be necessary if the neonate has only mild symptoms and the clinical picture is consistent with transient tachypnea of the newborn (TTN; eg, term or late preterm neonate born by cesarean delivery who has onset of tachypnea within one to two hours after birth with resolution over the subsequent 10 to 12 hours). (See "Transient tachypnea of the newborn", section on 'Clinical features'.)

The initial evaluation of the neonate with respiratory distress includes the following:

●History and physical examination, including pre- and postductal oxygen saturation

●Sepsis evaluation

●Chest imaging

In addition, if there is concern for cardiac disease or persistent pulmonary hypertension of the newborn (PPHN) based upon initial evaluation, echocardiography should be performed.

History — Relevant details from the history include gestational age, method of delivery, maternal risk factors for early-onset neonatal group B streptococcal (GBS) disease, and other pregnancy and/or delivery complications (eg, gestational diabetes, meconium stained amnionic fluid).

●TTN is a frequent cause of respiratory distress in term and late preterm neonates after cesarean 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 "Respiratory distress syndrome (RDS) in the newborn: Clinical features and diagnosis" and "Infants of mothers with diabetes (IMD)".)

●Infants born through meconium-stained amniotic fluid and those who have perinatal depression are at increased risk for 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 'Echocardiography' below and "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis", section on 'Diagnosis'.)

●Risk factors for early-onset GBS disease are discussed separately. (See "Prevention of early-onset group B streptococcal disease in neonates", section on 'Identification of pregnancies at increased risk for early-onset neonatal GBS' and "Group B streptococcal infection in neonates and young infants", section on 'Risk factors'.)

Sepsis evaluation — Because early-onset sepsis is an important cause of respiratory distress in the newborn, all neonates with significant respiratory distress and/or hypoxemia should undergo evaluation for neonatal sepsis and should receive empiric antibiotics pending culture results. The approach is described in detail separately. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Evaluation and initial management'.)

Chest imaging

●Chest radiography – Findings on chest radiograph 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 (image 1). Patchy infiltrates that clear within 24 to 48 hours may also reflect the fluid retention of TTN, but make initial differentiation from pneumonia problematic. (See "Transient tachypnea of the newborn", section on 'Radiographic features'.)

•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). (See "Respiratory distress syndrome (RDS) in the newborn: Clinical features and diagnosis", section on 'Diagnosis'.)

•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. (See "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis", section on 'Chest radiograph'.)

●Chest ultrasound – Neonatal chest ultrasonography is increasingly used in neonatology practice to evaluate for lung disease [9-14]. The presence of B-lines on ultrasound is suggestive of TTN [11,12]. The characteristic appearance of RDS is diffuse “white lung” [11,15]. Other findings that can be identified on lung ultrasound include focal consolidation suggestive of pneumonia, pleural effusion, and pneumothorax. A limitation of neonatal ultrasonography is that its diagnostic accuracy somewhat operator dependent.  

Echocardiography — Echocardiography should be performed if there is clinical concern congenital heart disease (CHD) or PPHN (eg, severe hypoxemia, differential pre- and postductal oxygen saturation, pathologic murmur, diminished or absent lower extremity pulses, cardiomegaly on chest radiograph).

In 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. (See "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis", section on 'Echocardiography'.)

The approach to identifying neonates with critical CHD is discussed in greater detail separately. (See "Identifying newborns with critical congenital heart disease" and "Newborn screening for critical congenital heart disease using pulse oximetry".)

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

●Transition from fetal life – 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.)

●Causes of neonatal respiratory distress

•Transitional disorders – Three common causes of respiratory distress in newborns are transient tachypnea of the newborn (TTN), respiratory distress syndrome (RDS), and persistent pulmonary hypertension of the newborn (PPHN).

-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 (image 1). (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. 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 "Respiratory distress syndrome (RDS) in the newborn: Clinical features and diagnosis".)

-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 usually associated with an underlying respiratory or systemic condition (eg, meconium aspiration syndrome [MAS], sepsis, pneumonia, perinatal asphyxia, congenital diaphragmatic hernia [CDH]) though 15 to 20 percent of cases are idiopathic. Neonates with PPHN typically present within the first 24 hours after birth with signs of respiratory distress (eg, tachypnea, retractions, and grunting) and cyanosis. Differential pre- and postductal oxygen saturation is a common finding. Echocardiography is required to confirm the diagnosis of PPHN and differentiate it from structural cyanotic congenital heart disease (CHD). (See "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis".)

•Other etiologies – Other causes of neonatal respiratory distress include (see 'Other etiologies' above):

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

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

-CHD (see "Identifying newborns with critical congenital heart disease" and "Diagnosis and initial management of cyanotic heart disease in the newborn")

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

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

-Neonatal abstinence syndrome (see "Prenatal substance exposure and neonatal abstinence syndrome (NAS): Management and outcomes")

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

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

-Congenital pulmonary airway malformation (see "Congenital pulmonary airway malformation")

-Other rare congenital primary pulmonary disorders (eg, primary ciliary dyskinesia, genetic surfactant disorders, inherited pulmonary alveolar proteinosis, alveolar capillary dysplasia) (see "Classification of diffuse lung disease (interstitial lung disease) in infants and children", section on 'Disorders more prevalent in infancy')

●Diagnostic approach – The initial evaluation of the neonate with respiratory distress includes the following (see 'Diagnostic approach' above):

•History and physical examination, including pre- and postductal oxygen saturation (see 'History' above)

•Sepsis evaluation (see "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Evaluation and initial management')

•Chest imaging (see 'Chest imaging' above)

In addition, echocardiography should be performed if there is clinical concern for CHD or PPHN (eg, severe hypoxemia, differential pre- and postductal oxygen saturation, pathologic murmur, diminished or absent lower extremity pulses, cardiomegaly on chest radiograph). (See 'Echocardiography' above.)

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.