Transient tachypnea of the newborn

INTRODUCTION — Transient tachypnea of the newborn (TTN) is a parenchymal lung disorder characterized by pulmonary edema resulting from delayed resorption and clearance of fetal alveolar fluid. It is the most common cause of respiratory distress in late preterm and term infants and is generally a benign, self-limited condition.

The clinical features, diagnosis, and management of TTN will be discussed here.

An overview of neonatal conditions that present with respiratory distress is found separately (see "Overview of neonatal respiratory distress and disorders of transition") as well as topics that discuss other neonatal respiratory disorders.

●Neonatal respiratory distress syndrome. (See "Respiratory distress syndrome (RDS) in the newborn: Clinical features and diagnosis".)

●Persistent pulmonary hypertension of the newborn. (See "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis".)

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

●Neonatal pneumonia. (See "Neonatal pneumonia" and "Group B streptococcal infection in neonates and young infants", section on 'Pneumonia'.)

NORMAL ALVEOLAR FLUID CLEARANCE — The normal process of clearing fetal alveolar fluid begins before term birth and continues through labor and after delivery. From the onset of labor to the delivery of the term newborn, approximately 100 mL of fetal lung liquid is cleared [1].

During late gestation, in response to increased concentrations of catecholamines and other hormones, the mature lung epithelium switches from actively secreting chloride and liquid into the air spaces to actively reabsorbing sodium and liquid (figure 1) [2,3]. Increased oxygen tension at birth increases gene expression of the epithelial sodium channel leading to the enhanced sodium and water absorption [3]. In immature lungs, reduced gene expression of this channel contributes to the inability to switch from fluid secretion to absorption. However, glucocorticoids can upregulate gene expression resulting in active absorption through sodium channels [3].

Passive resorption of liquid also occurs after birth because of differences among the oncotic pressure of air spaces, interstitium, and blood vessels. The majority of water transport across the apical membrane is thought to occur through aquaporin 5 (AQP5) water channels [4].

PATHOPHYSIOLOGY — TTN is a parenchymal lung disorder characterized by pulmonary edema resulting from delayed resorption and clearance of fetal alveolar fluid. In TTN, delayed resorption of fetal lung fluid fills the air spaces and moves into the interstitium, where it pools in perivascular tissues and interlobar fissures.

The excess lung water in TTN results in decreased pulmonary compliance. Tachypnea develops to compensate for the increased work of breathing associated with reduced compliance. In addition, accumulation of fluid in the peribronchiolar lymphatics and interstitium promotes partial collapse of the bronchioles with subsequent air trapping. Continued perfusion of poorly ventilated alveoli leads to hypoxemia, and alveolar edema reduces ventilation, sometimes resulting in hypercapnia. Eventually fluid is cleared by lymphatic drainage or absorbed into small blood vessels.

The underlying mechanism leading to delayed absorption of alveolar fluid in neonates with TTN is unknown.

●Decreased surfactant function has been proposed as contributing to the pathophysiology of TTN. In one small study of term infants delivered via elective cesarean delivery, patients with TTN compared with age-matched controls were more likely to have lower surfactant function as determined by gastric aspirate measurement of lamellar body count and stable microbubble test [5]. However, further studies are needed to confirm these findings.

●Reduced nitric oxide (NO) has also been proposed as a contributing cause. Asymmetric dimethylarginine (ADMA) is an endogenous NO synthase inhibitor. Increased ADMA concentration may reduce NO synthesis, leading to increased pulmonary vascular resistance associated with fetal lung fluid retention and resulting in prolonged duration of tachypnea. In one small study, ADMA levels were elevated in newborns with TTN compared with healthy newborns [6].

EPIDEMIOLOGY — TTN is the most common cause of respiratory distress in term and late-preterm infants, with an estimated incidence of 4.0 to 5.7 per 1000 term births [1,7-9]. The incidence appears to be higher in preterm infants, although it is more difficult to ascertain the risk due to other conditions with respiratory distress [1]. (See "Overview of neonatal respiratory distress and disorders of transition".)

Additional reported risk factors for TTN besides prematurity include:

●Cesarean delivery – Cesarean delivery is associated with a higher risk of TTN than vaginal delivery, thought to be due to reduced alveolar fluid clearance. (See "Physiologic transition from intrauterine to extrauterine life", section on 'Alveolar fluid clearance'.)

•In a single center review of 29,669 consecutive deliveries from 1992 to 1999, TTN occurred in more infants after cesarean deliveries (n = 4301) than after vaginal delivery (n = 21,017, 3.5 versus 1.1 percent, odds ratio [OR] 3.3, 95% CI 2.6-3.9) [10].

•In a population-based German study of almost 240,000 term deliveries from 2001 to 2005, the incidence of TTN was 5.9 cases per 1000 singleton births [11]. Elective cesarean section without labor was the most significant risk factor and the risk increased with each additional week of gestation between 37 and 40 weeks. For the newborns with TTN in this cohort, 42 percent were delivered by elective cesarean delivery compared with the 9.2 percent of TTN reported in the German perinatal registry.

●Antenatal corticosteroids – The administration of antenatal corticosteroid therapy appears to reduce the rate of TTN in late preterm and term infants. However, it remains uncertain whether the benefit of reducing TTN outweighs the potential adverse effects of corticosteroid therapy. (See "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery", section on '34+0 or more weeks'.)

●Other reported risk factors:

•Maternal diabetes and obesity – TTN occurs two to three times more often in infants of mothers with diabetes mellitus. The mechanism may be related to decreased fluid clearance in the fetal lung, although cesarean delivery, which is more frequently performed in pregnancies of diabetic mothers, is likely a contributing factor. (See "Infants of mothers with diabetes (IMD)", section on 'Other causes of respiratory distress'.)

Maternal obesity without chronic disease has been associated with TTN [12,13].

•Maternal asthma – Maternal asthma has been reported to be a risk factor for TTN. In one study, 493 infants of asthmatic mothers appear to be more likely to have TTN than a control sample of infants with mothers without asthma (OR 1.8, 95% CI 1.4-2.4) [14].

CLINICAL FEATURES

Clinical manifestations — The onset of TTN is usually between the time of birth and two hours after delivery. Tachypnea (respiratory rate greater than 60 breaths per minute) is the most prominent feature. Infants with more serious disease will have cyanosis and increased work of breathing, manifested by nasal flaring, mild intercostal and subcostal retractions, and expiratory grunting. The anterior-posterior diameter of the chest may be increased.

Breath sounds in affected infants typically are clear, without rales or rhonchi. Infants with mild to moderate TTN are symptomatic for 12 to 24 hours, but signs may persist as long as 72 hours in severe cases. Infants rarely require a supplemental oxygen concentration greater than 40 percent to achieve adequate oxygenation. Affected infants also rarely require additional respiratory support (ie, noninvasive continuous positive pressure or mechanical ventilation). (See 'Respiratory support' below.)

Radiographic features

●Chest radiograph – The characteristic findings on chest radiograph include increased lung volumes with flat diaphragms, mild cardiomegaly, and prominent vascular markings in a sunburst pattern originating at the hilum. Fluid often is seen in the interlobar fissures, and pleural effusions may be present. Alveolar edema may appear as fluffy densities. There are no areas of alveolar densities or consolidations (image 1).

●Lung ultrasound – Lung ultrasonography is an accurate and reliable tool for diagnosing TTN and is used in many centers, including ours [15]. Findings suggestive of TTN include pulmonary edema, compact B lines (hyperechoic lines arising from the pleural surface), double lung point (sharp boundary between relatively aerated superior lung fields and coalescent B‐lines in the inferior fields), and a regular pleural line without consolidation [16,17]. (See "Overview of neonatal respiratory distress and disorders of transition", section on 'Chest imaging'.)

DIAGNOSIS — TTN is a clinical diagnosis (typically made in late preterm and term infants) based on respiratory distress presenting shortly after delivery with characteristic findings on chest imaging. The diagnosis is confirmed with resolution of symptoms within 12 to 24 hours. (See 'Radiographic features' above.)

DIFFERENTIAL DIAGNOSIS — TTN is a benign disorder, and pathologic conditions that also present with respiratory distress must be excluded. Other common causes of respiratory distress in the newborn include infections (eg, sepsis, pneumonia) and noninfectious causes (eg, respiratory distress syndrome [RDS], congenital heart disease) (table 1).

Typically, infants with TTN do not have persistent respiratory distress beyond 24 to 48 hours, require high oxygen concentration (greater than 60 percent) supplementation or additional respiratory support (eg, mechanical ventilation). These clinical features and chest radiographic findings typically differentiate TTN from the following more serious conditions:

●Pneumonia – Chest radiography differentiates pneumonia from TTN as neonatal pneumonia is characterized by alveolar densities with air bronchograms or patchy infiltrates, which are not seen in TTN. (See "Neonatal pneumonia" and 'Radiographic features' above.)

●Sepsis – Neonates with sepsis and respiratory distress are differentiated from those with TTN with the persistence of additional symptoms and the lack of the characteristic chest radiographic findings of TTN. A positive blood culture confirms the diagnosis. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Clinical manifestations'.)

●Congenital cardiac disease – The presence and degree of respiratory distress varies based on the underlying cardiac lesion. In some cases, tachypnea, increased work of breathing, and feeding difficulties occur due to pulmonary edema from a rapid increase in pulmonary blood flow, which will persist. Other infants with mild to moderate pulmonary overcirculation frequently have tachypnea without significant increased work of breathing at rest but become distressed during feeding. TTN is distinguished from congenital heart disease by physical findings (eg, heart murmur, abnormal precordial activity), chest radiography, pre- and postductal pulse oximetry, and echocardiography. (See "Identifying newborns with critical congenital heart disease", section on 'Respiratory symptoms'.)

●Respiratory distress syndrome (RDS) – RDS due to surfactant deficiency is more common in very preterm infants (gestational age <32 weeks) and infants with RDS usually have a characteristic chest radiograph of a ground glass appearance with air bronchograms that differentiates it from TTN (image 2). (See "Respiratory distress syndrome (RDS) in the newborn: Clinical features and diagnosis", section on 'Clinical manifestations'.)

MANAGEMENT

Supportive care — Supportive measures include:

●Neutral thermal environment.

●Nutrition – Respiratory rates greater than 60 to 80 breaths per minute or increased work of breathing preclude oral feeding; orogastric tube feeding or intravenous fluids should be provided in such patients.

Respiratory support — In our center, supplemental oxygen is provided by hood or nasal cannula. Newborns are monitored with pulse oximetry and oxygen therapy is adjusted to maintain peripheral oxygen saturation (Sp02) between 90 and 95 percent. Infants with TTN rarely require a fraction of inspired oxygen (FiO2) >0.4. If the required FiO2 exceeds 0.4 or the infant has increased work of breathing and/or significant tachypnea, we provide nasal continuous positive airway pressure (nCPAP) to improve the work of breathing. However, it is unusual for infants with TTN to require this level of respiratory support. Thus, the clinician should consider other causes of respiratory distress (sepsis, respiratory distress syndrome) if the newborn requires escalating support. (See 'Differential diagnosis' above.)

There are limited data on the effect of different types of noninvasive respiratory support in neonates with TTN [18,19]. A 2020 systematic review identified three trials involving 150 infants [18]. The data could not be pooled because of differences in study design. One trial compared nCPAP with a nonstandard therapy (nasal high‐frequency ventilation). In the other two trials, the following findings were noted:

●nCPAP versus supplemental oxygen without positive pressure – In a trial of 64 neonates with TTN randomized to nCPAP or supplemental oxygen without positive pressure, nCPAP reduced the duration of tachypnea (9 versus 30 hours) and there was a nonsignificant trend towards reduced hospital length of stay (3.3 versus 4.1 days) [20]. Only one infant in the trial required invasive ventilation (in the control group).

●nCPAP versus nasal intermittent positive pressure ventilation (NIPPV) – A trial involving 40 neonates with TTN who were randomized to nCPAP or NIPPV did not detect significant differences in duration of symptoms (63 versus 68 hours, respectively), oxygen therapy (29 versus 32 hours), or hospital length of stay (5.4 versus 6.2 days) between the two groups [21]. Few infants in either group required intubation (one infant in the nCPAP group versus four in the NIPPV group). There were two episodes of pneumothorax (one in each group).

There are no available clinical trial data on the use of high-flow nasal cannula (HFNC) in this setting.

Despite the paucity of data, we continue to use nCPAP for infants with severe and persistent TTN based on clinical experience and indirect evidence from other conditions of the benefit of positive pressure support. We prefer nCPAP to NIPPV as the latter requires a ventilator for administration, which increases the cost and complexity of use. HFNC can also provide positive pressure support but we do not use this modality because the delivered concentration of oxygen and pressure to the infant is highly variable and difficult to monitor. (See "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn", section on 'Respiratory support devices'.)

Fluid management

●Fluid restriction – It is uncertain whether fluid restriction is beneficial in the management of TTN [19,22]. Nevertheless, based on the proposed pathogenesis, we restrict fluid intake for infants with TTN during the first day of life. For late preterm and term infants, restricted fluid therapy is ≤65/mL/kg per day. For preterm infants (GA<34 weeks), fluid therapy is restricted to ≤80 mL/kg per day. (See "Fluid and electrolyte therapy in newborns".)

A systematic review identified four trials comparing restricted versus standard fluid management in 317 late preterm and term infants with TTN [22]. In the two trials (n = 172 infants) that reported duration of supplemental oxygen therapy, there was a nonsignificant trend towards a shorter duration with restricted versus standard fluid therapy (mean difference [MD] 13 hours shorter, 95% CI 33 hours shorter to 7 hours longer). In the three trials (n = 242 infants) that reported rates of mechanical ventilation, few infants in either group required this intervention (five infants [4 percent] in the restricted fluid group versus seven [6 percent] in the standard fluid group). Similarly, in the two trials that reported use of noninvasive ventilation (ie, nCPAP), the small number of events precludes drawing any conclusion (four infants [5 percent] in the restricted fluid group versus 10 [13 percent] in the standard fluid).

However, further studies are needed to confirm whether fluid restriction is a safe and effective intervention for TTN.

●Diuretic therapy – We suggest not administering diuretic therapy in infants with TTN given the limited evidence suggesting it provides no additional benefit and the known side effects of this therapy. In a meta-analysis of two trials (n = 100), duration of symptoms was similar in infants treated with diuretic therapy compared with control [23]. Length of hospitalization was also similar in both groups.

Adjunctive therapy — The following adjunctive therapies should not be routinely administered as they have not been shown to conclusively improve outcome in infants with TTN

●Beta agonists – Clinical trials with important limitations have suggested a possible benefit of beta-agonist therapy in infants with TTN. However, since the benefit is uncertain and there are known side effects of this therapy, we suggest not using it routinely in the management of TTN, which is typically a self-limited and benign condition.

In a meta-analysis of four trials (338 infants) comparing albuterol (salbutamol) with normal saline, albuterol therapy resulted in shorter duration of oxygen therapy (MD -19 hours, 95% CI 15 to 24 hours shorter) and shorter hospital stay (MD 1.5 days, 95% CI 1.2 to 1.8 days shorter) [24]. Two trials (228 infants) reported duration of respiratory support and found shorter duration in the albuterol group (MD 9 hours, 95% CI 4 to 14 hours shorter). Three trials (254 infants) reported rates of mechanical ventilation, but the small number of events (two in the albuterol group; three in the control group) preclude drawing any conclusion. One small trial (46 infants) did not detect a significant difference in need for CPAP (39 versus 53 percent; relative risk [RR] 0.73, 95% CI 0.38-1.39). The trials in this meta-analysis had important limitations, including small numbers, incomplete reporting of outcomes, and unclear methodology regarding blinding and allocation concealment. Thus, the certainty of these findings is low.

●Inhaled corticosteroid therapy – It remains inconclusive whether inhaled corticosteroid therapy is beneficial for infants with TTN. As a result, we suggest not using inhaled corticosteroids routinely to treat TTN given the lack of data showing effectiveness and their potential for adverse effects. A systematic review identified only one trial (n = 49) that compared inhaled corticosteroids (budesonide) with placebo, which reported no additional benefit regarding the need for nCPAP (0.4 versus 0.4 percent, RR 1.27, 95% CI 0.65-2.51) and for mechanical ventilation (RR 0.52, 95% CI 0.05-5.38) [25].

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

●Pathophysiology – Transient tachypnea of the newborn (TTN) is a parenchymal lung disorder characterized by pulmonary edema resulting from delayed resorption and clearance of fetal alveolar fluid. (See 'Pathophysiology' above.)

●Epidemiology – TTN is the most common cause of respiratory distress immediately after delivery in late preterm and term infants with an estimated incidence of 4 to 6 per 1000 term births. Reported risk factors include prematurity, birth by cesarean delivery without labor, and maternal diabetes and obesity. (See 'Epidemiology' above.)

●Presentation – The typical presentation of TTN is onset of tachypnea (respiratory rate >60 breaths per minute) within two hours after delivery in late preterm and term infants. Infants may also be cyanotic and have increased work of breathing (ie, nasal flaring, intercostal and subcostal retractions, and expiratory grunting). Breath sounds generally are clear, without rales or rhonchi. TTN is typically a benign condition and symptoms generally resolve after 12 to 24 hours, but may persist as long as 72 hours in severe cases. (See 'Clinical manifestations' above.)

●Diagnosis – TTN is a clinical diagnosis based on the onset of respiratory distress shortly after delivery with characteristic findings on chest imaging that include increased lung volumes with flat diaphragms, mild cardiomegaly, and prominent vascular markings in a sunburst pattern originating at the hilum (image 1). (See 'Diagnosis' above and 'Radiographic features' above.)

●Differential diagnosis – TTN is a diagnosis of exclusion and it needs to be distinguished from more serious causes of neonatal respiratory distress including pneumonia, congenital cardiac disease, respiratory distress syndrome (RDS), and sepsis (table 1). These disorders are differentiated from TTN by their clinical features (persistent and more serious respiratory disease) and chest radiographic findings. (See 'Differential diagnosis' above.)

●Management – TTN is a benign, self-limited condition. Supportive management includes:

•Maintenance of a neutral thermal environment.

•Nutrition – Most affecting infants are able to feed by mouth. However, for infants with marked tachypnea (respiratory rate >60 breaths per minute), oral feeding is avoided and nutrition is provided either by orogastric feeds or intravenous nutrition.

•Respiratory support

-Oxygen supplementation is provided by hood or nasal cannula to maintain oxygen saturation between 90 and 95 percent. (See 'Management' above.)

-For newborns who require a fraction of inspired oxygen (FiO2) >0.4 and/or have significant work of breathing (ie, nasal flaring, intercostal and subcostal retractions, and expiratory grunting), we suggest nasal continuous positive airway pressure (nCPAP) rather than ongoing oxygen therapy alone (Grade 2C). Nasal intermittent positive pressure ventilation (NIPPV) and high-flow nasal cannula (HFNC) are reasonable alternatives to nCPAP. (See 'Respiratory support' above.)

•Fluid restriction – We suggest modest fluid restriction (ie, 80 mL/kg per day) rather than standard fluid intake for the first day of life (Grade 2C). (See 'Fluid management' above.)

•No role for diuretic therapy – We suggest not using diuretic therapy for the treatment of TTN (Grade 2C). Diuretics do not appear to hasten symptom resolution and they have known adverse effects. (See 'Fluid management' above.)