Transient Tachypnea of the Newborn

Transient tachypnea of the newborn (TTN) is a self-limited disease commonly seen in neonates throughout the world and is encountered by all physicians who take care of newborn infants. Infants with transient tachypnea of the newborn present within the first few hours of life with tachypnea and other signs of respiratory distress, increased oxygen requirement, and ABGs that do not reflect carbon dioxide retention. When managing transient tachypnea of the newborn, it is imminent to observe for development of respiratory fatigue and signs of clinical deterioration that may suggest some other diagnoses. See the image below.

Transient Tachypnea of the Newborn. A supine anteroposterior chest radiograph of an infant with transient tachypnea of the newborn (TTN). Note the reticular appearance of the film with mild cardiomegaly and obvious interstitial fluid.

Noninfectious acute respiratory disease develops in approximately 1% of all newborn infants and results in admission to a critical care unit. Transient tachypnea of the newborn (TTN) is the result of a delay in clearance of fetal lung liquid. In the past, respiratory distress was thought to be a problem of relative surfactant deficiency but is now characterized by an airspace-fluid burden secondary to the inability to absorb fetal lung liquid.

In vivo experiments have demonstrated that lung epithelium secretes Cl- and fluid throughout gestation but develops the ability to actively reabsorb Na+ only during late gestation. At birth, the mature lung switches from active Cl- (fluid) secretion to active Na+ (fluid) absorption in response to circulating catecholamines; evidence suggests glucocorticoids play a role in this switch. Changes in oxygen tension augment the Na+ -transporting capacity of the epithelium and increase gene expression for the epithelial Na+ channel (ENaC). The inability of the immature fetal lung to switch from fluid secretion to fluid absorption results, mainly because of immaturity in the expression of ENaC, which can be up-regulated by glucocorticoids.[1] Glucocorticoids induce lung Na+ reabsorption most likely through the fetal lung alveolar ENaC channel in late gestational age.[2]

Both pharmacologic blockade of the lung's ENaC channel and genetic knockout experiments using mice deficient in the ENaC pore-forming subunit have demonstrated the critical physiologic importance of lung Na+ transport at birth. When Na+ transport is ineffective, newborn animals develop respiratory distress; hypoxemia; fetal lung liquid retention; and, in the case of the ENaC knockout mice, death. Bioelectrical studies of human infants' nasal epithelia demonstrate that both transient tachypnea of the newborn and respiratory distress syndrome (RDS) involve defective amiloride-sensitive Na+ transport.[3, 4]

Mature newborns who have normal transitions from fetal to postnatal life have mature surfactant and lung epithelial systems. Transient tachypnea of the newborn occurs in mature newborns with mature surfactant pathways and poorly developed respiratory epithelial Na+ transport, whereas neonatal RDS occurs in infants with both premature surfactant pathways and immature Na+ transport. Although, full-term neonates may have lower lamellar body counts, suggesting diminished surfactant function and association with prolonged tachypnea of newborns.[5]

Fetal lung fluid clears by 35% a few days prior to birth, owing to changes in the ENaC; by around 30% during active labor owing to mechanical transpulmonary forces and catecholamine surge; and around 35% is cleared postnatally during active crying and breathing. An infant born by cesarean delivery is at risk of having excessive pulmonary fluid as a result of not having experienced all of the stages of labor and subsequent lack of appropriate catecholamine surge, which results in low release of counter-regulatory hormones at delivery. The result is alveoli with retained fluid that inhibit gas exchange.

Transient tachypnea of the newborn (TTN) results from delayed absorption of fetal lung fluid following delivery. The disorder is commonly observed following birth by cesarean delivery.

Cesarean delivery

Cesarean delivery is associated with increased risk of transient tachypnea of the newborn regardless of whether the cesarean delivery was preceded by labor or not. Labor prior to cesarean delivery is not protective of transient tachypnea of the newborn.[6]

Studies using lung mechanical measurements were performed in infants born by either cesarean or vaginal delivery. Milner et al noted that the mean thoracic gas volume was 32.7 mL/kg in infants born vaginally and 19.7 mL/kg in infants born via cesarean delivery.[7] Important to note is that chest circumferences were the same. Milner et al noted that the infants born via cesarean delivery had higher volumes of interstitial and alveolar fluid compared with those born vaginally, even though the overall thoracic volumes were within the reference range.

Epinephrine release during labor affects fetal lung fluid. In the face of elevated epinephrine levels, the chloride pump responsible for lung liquid secretion is inhibited, and the sodium channels that absorb liquid are stimulated. As a result, net movement of fluid from the lung into the interstitium occurs.[8, 9] Therefore, cesarian delivery without labor and subsequent lack of this normal surge of counter-regulatory hormones limit the excursion of pulmonary fluid.

Maternal asthma and smoking

Demissie et al performed a historical cohort analysis on singleton live deliveries in New Jersey hospitals from 1989-1992.[10] After controlling for confounding effects of important variables, infants of mothers with asthma were more likely to exhibit transient tachypnea of the newborn than infants of mothers in the control group.

Schatz et al studied a group of 294 pregnant women with asthma and a group of 294 pregnant women without asthma.[11] Both groups had normal pulmonary function test results and were matched for age and smoking status. transient tachypnea of the newborn was found in 11 infants (3.7%) of mothers with asthma and in 1 infant (0.3%) of a mother from the control group. No significant differences between asthmatic and matched control subjects in other transient tachypnea of the newborn risk factors were observed.

Gundogdu studied the effect of sibling asthma on 1318 newborns with transient tachypnea of the newborn.[12] Prelabor cesarean section and maternal asthma were common risk factors for these newborns, and there was an association between sibling asthma and the development of transient tachypnea of the newborn in the infants, even when their mothers were nonasthmatics.[12]

Prematurity

Late preterm infants are at higher risk of developing transient tachypnea of the newborn compared with full-term infants, probably because of immaturity of ENaC transition, lack of lamellar bodies for surfactant production, and overall lung epithelium immaturity.[13, 14]  The risk of adverse respiratory outcomes in late preterm infants is particularly higher for those delivered after 35 weeks' gestatoin and whose mothers did not receive antenatal steroids.[15]

Gestational diabetes in itself does not appear to be a major contributor to respiratory distress syndrome in infants born late preterm.[16] ​ Independent factors that raise the risk of respiratory morbidity in these infants are prematurity and cesarean birth.

Male sex and macrosomia

Male sex and macrosomic infants born to diabetic mothers have been associated with increased risk of transient tachypnea of the newborn.

Other factors

Excessive maternal sedation, perinatal asphyxia, and elective cesarean delivery without preceding labor, low Apgar scores, and prolonged rupture of membranes are frequently associated with transient tachypnea of the newborn.

United States data

Approximately 1% of infants have some form of respiratory distress that is not associated with infection. Respiratory distress includes both respiratory distress syndrome (RDS) (ie, hyaline membrane disease) and transient tachypnea of the newborn. Of this 1%, approximately 33-50% have transient tachypnea of the newborn (TTN).

Race-, sex-, and age-related demographics

No racial predilection has been reported,  and male neonates are more affected than females.

Clinically, transient tachypnea of the newborn presents as respiratory distress in full-term or near-term infants.

Morbidit/mortality

Transient tachypnea of the newborn (TTN) is generally a self-resolving disorder with excellent prognosis. It frequently resolves over a 24-hour to 72-hour period.

However, this condition has been associated with subsequent respiratory morbidity, with a significantly increased risk of a wheezing disorder in childhood.

Complications

Some infants may develop hypoxia, respiratory fatigue, and acidosis. Occasionally, air leaks (eg, a small pneumothorax or pneumomediastinum) may be seen in infants who have increased work of breathing. Hence, any infant who does not follow the typical course of transient tachypnea of the newborn and develops any concerning symptoms must be re-evaluated.

Infants delivered by elective cesarean section prior to 39 weeks' gestation may develop pulmonary hypertension and may require extracorporeal membrane oxygenation (ECMO).[17]

Several reports suggest that transient tachypnea of the newborn is a risk factor for future wheezing syndromes in childhood and may not be as transient as previously thought. Although Liem et al hypothesize that genetic and environmental interactions synergistically predispose these children for future wheeze, prospective studies are required to better define this association.[18]

Inform parents that transient tachypnea of the newborn (TTN) is usually a self-limited disorder and is not life threatening.

New data link transient tachypnea of the newborn to the later development of childhood asthma. Birnkrant et al studied the association between childhood asthma and transient tachypnea of the newborn in a nested cohort of 2137 term newborns who were subsequently diagnosed with asthma and a similar number of birthday-matched controls.[19] After adjustment for confounding factors, transient tachypnea of the newborn was significantly associated with the diagnosis of childhood asthma. The adjusted odds ratio was 1.5 (95% CI, 1.13-1.99; P = .005). The association of transient tachypnea of the newborn and asthma was statistically strongest among nonwhite male infants whose mothers lived at an urban address and did not have asthma. Thus, parents should be made aware that their child has a small risk of subsequently developing childhood asthma, especially if the child is male.

The maternal history in transient tachypnea of the newborn (TTN) consists of cesarian delivery without labor or precipitous delivery.

Signs of respiratory distress (eg, tachypnea, nasal flaring, grunting, retractions, hypoxia, increased oxygen requirement and cyanosis in extreme cases) become evident shortly after birth.

The disorder is indeed transient, usually resolved within 72 hours after birth.

Physical findings in infants with transient tachypnea of the newborn (TTN) include tachypnea with variable grunting, flaring, and retractions.

The infant usually does not appear to be in acute distress and often is described as having "quiet" tachypnea.

Extreme cases may exhibit severe hypoxia and cyanosis.

A study investigating the risk factors for duration of tachypnea in patients with transient tachypnea of the newborn reported that peak respiratory rate of more than 90 breaths per minute during the first 36 hours of life was associated with prolonged tachypnea lasting more than 72 hours.[20]

The following studies are indicated in transient tachypnea of the newborn (TTN).

Arterial blood gas (ABG)

An ABG assessment is important to ascertain the degree of gas exchange and acid-base balance.

Consider an intraarterial catheter, such as an umbilical artery catheter, if the infant's inspired fraction of oxygen exceeds 40%.

Hypoventilation is very uncommon, and partial carbon dioxide tensions are usually normal because of the tachypnea. However, a rising carbon dioxide tension in an infant with tachypnea may be a sign of fatigue and impending respiratory failure or a complication such as a pneumothorax.

Pulse oximetry

Continuously monitor infants with pulse oximetry for assessment of oxygenation.

Pulse oximetry allows the clinician to adjust the level of oxygen support needed to maintain appropriate saturation.

Persistently increased oxygen requirement (FiO 2 >40%) may be an indication for surfactant replacement.

Other tests

Few biochemical markers have been shown to be effective in predicting the severity of transient tachypnea of the newborn, such as lactate, lactate dehydrogenase (LDH),[21] and plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP).[22]

Levels of ischemia-modified albumin (IMA) appear to have potential as markers for predicting transient tachypnea of the newborn and disease severity. A study of 47 infants with this condition found significantly higher levels in infants with transient tachypnea of the newborn relative to control infants without respiratory symptoms, as well as in infants on nasal continuous positive airway pressure (CPAP) compared to those on supplemental oxygen therapy.[23]

Chest radiography

Chest radiography is the diagnostic standard for transient tachypnea of the newborn.

The characteristic findings include prominent perihilar streaking, which correlates with the engorgement of the lymphatic system with retained lung fluid, and fluid in the fissures. Small pleural effusions may be seen. Patchy infiltrates have also been described.

Follow-up chest radiography may be necessary if the clinical history suggests meconium aspiration syndrome or neonatal pneumonia or if respiratory status worsens.

Lung ultrasonography

One study showed the utility of lung sonogram in diagnosing transient tachypnea of the newborn with sensitivity and specificity of 100%. Copetti et al described the sonographic landmark finding of transient tachypnea of the newborn as “double lung point”.[24]

Lung ultrasonography appears to be useful in neonates with suspected or confirmed coronavirus disease 2019 (COVID-19). In a 2020 study that comprised data from 27 infants, investigators reported the following findings[25] :

• Infants who had pulmonary symptoms but were negative for COVID-19 presented with transient tachypnea of the newborn and respiratory distress syndrome.
• In these COVID-19-negative infants, lung ultrasonography some showed a pattern with A lines, few B lines, a thin linear pleural line, and no pleural effusion (normal), whereas others showed coalescent B lines and areas of opacity.
• Of infants positive for COVID-19, the lung sonograms in two revealed several coalescent B lines, pleural thickening, and areas of opacity.

Echocardiography

Echocardiogram is warranted in an infant with persistent tachypnea for more than 5-6 days to rule out congenital cardiac anomalies and cardiac function.

Prevention

Schedule elective cesarean delivery until 39 weeks' gestation or later or wait for the onset of spontaneous labor. Also, consider establishing fetal maturity as appropriate for elective cesarean delivery prior to 39 weeks' gestation.

Transfer

An appropriately trained support staff is needed to treat infants with transient tachypnea of the newborn. Infants with transient tachypnea of the newborn and pneumonia or meconium aspiration may have similar clinical presentations. Therefore, staff members must be competent in recognizing worsening respiratory distress or impending failure and must be able to appropriately resuscitate the infant.

Transfer is generally indicated by the need for a higher level of observation and/or care.

Hein et al have recommended the “rule of 2 hours,” whereby the newborn is observed for 2 hours after the onset of respiratory distress. The baby may be referred to a higher facility if the chest radiograph does not appear normal, the baby is worsening clinically, the baby requires more than 40% oxygen to maintain normal oxygen saturation, or there is no improvement after 2 hours of all feasible interventions.[26]

Medical care of transient tachypnea of the newborn (TTN) is supportive. As the retained lung fluid is absorbed by the infant's lymphatic system, the pulmonary status improves.

Supportive care includes intravenous fluids and gavage feedings until the respiratory rate has decreased enough to allow oral feedings. Supplemental oxygen to maintain adequate arterial oxygen saturation, maintenance of thermoneutrality, and an environment of minimal stimulation are the therapies necessary in these infants. ABG assessments should be periodically repeated, especially if the infant's condition worsens. Similarly, chest radiography should be repeated if clinical decompensation is observed.

As transient tachypnea of the newborn resolves, the infant's tachypnea improves, oxygen requirement decreases, and chest radiography shows resolution of the perihilar streaking.

Infants with transient tachypnea of the newborn may have signs that last from a few hours to several days. Rarely, an infant develops a worsening picture of respiratory distress after several days. This may require more aggressive support including the use of continuous positive airway pressure (CPAP) or mechanical ventilation.

A clinical trial that examined the role of inhaled epinephrine for the treatment of transient tachypnea of the newborn found no adverse events when inhaled epinephrine was administered to full-term newborns with moderate-to-severe transient tachypnea of the newborn.[27] More importantly, they did not detect any difference in rate of resolution of tachypnea in placebo and inhaled epinephrine groups. At this time, inhaled epinephrine is not recommended for infants with transient tachypnea of the newborn.

While furosemide is a strong diuretic and is known to cause lung fluid resorption, oral use of this medication has not shown any benefit in either the severity or duration of the illness or length of hospitalization. Administering furosemide intravenously, or even to the mother before cesarean delivery, might have a more powerful effect and may merit investigation. This, however, is not recommended as a standard treatment at this time.[28]

Genetic variations in the beta-adrenergic receptor–encoding genes leading to decreased function at the receptor level has been proposed as the link between transient tachypnea of the newborn and future predisposition to asthma in some patients. However, inhaled beta-agonists are currently not recommended as standard therapy in transient tachypnea of the newborn.[29] In one study, inhaled salbutamol therapy did not shorten the duration of tachypnea significantly in infants diagnosed with transient tachypnea of the newborn.[30] However, inhaled beta-agonists are not recommended as standard therapy in transient tachypnea of the newborn.

Respiratory rate at 36 hours (>90 breaths/minute, RRpeak) was found to be associated with 7.04-fold of prolonged tachypnea and longer duration of hospitalization.[31]

After resolution of transient tachypnea of the newborn, focus further inpatient care on routine newborn management, including temperature regulation and feeding.

Infants with transient tachypnea of the newborn occasionally may require consultation by a neonatologist.

Consider this consultation if the fraction of inspired oxygen exceeds 40%, if metabolic acidosis or respiratory acidosis is present, if CPAP or mechanical ventilation is required, if the infant begins to display fatigue (periodic breathing or apnea), or if the infant fails to improve by age 48-72 hours.

Infants with transient tachypnea of the newborn are generally supported by intravenous fluids or gavage feedings.

Infants with significant distress have poor bowel motility and require intravenous therapy.

Oral feedings are withheld until the respiration has improved.

The use of medications in transient tachypnea of the newborn (TTN) is minimal. It is difficult to rule out sepsis or pneumonia clinically, in the presence of signs of respiratory distress, especially in the absence of risk factors for infection in the infant. Therefore, empiric antibiotics are often used for 48 hours after birth, until sepsis has been ruled out.

Studies suggest that routine use of empirical antibiotics may not be warranted in late preterm and full-term infants with transient tachypnea of the newborn in the absence of specific infectious risk factors and a negative C-reactive protein.[32] Infants who received antibiotics stayed longer in the hospital.[33, 34]

Diuretics[28] and inhaled corticosteroids[35] have not been shown to be beneficial.

Class Summary

These agents are used when sepsis is clinically suggested. Antibiotics generally consist of a penicillin (usually ampicillin) and an aminoglycoside (usually gentamicin). Choices are based on local flora and antibiotic sensitivities. Dosage amounts and intervals are based on postmenstrual age (PMA), measured in weeks, and postnatal age, measured in days.

Ampicillin (Omnipen-N)

A penicillin antibiotic with activity against gram-positive and some gram-negative bacteria. Ampicillin binds to penicillin-binding proteins (PBPs), inhibiting bacterial cell wall growth.

Gentamicin

Provides gram-negative aerobic coverage. Gentamicin also provides synergistic activity with penicillins against gram-positive bacteria including group B Streptococcus and Enterococcus. Gentamicin inhibits protein synthesis by irreversibly binding to bacterial 30S and 50S ribosomes.

Given as IV infusion by syringe pump over 30 min. Administer as separate infusion from penicillin-containing compounds.

IM injection is associated with variable absorption, especially in VLBW infants.