Pediatrics

Transient tachypnea of the newborn

OVERVIEW: What every practitioner needs to know

Are you sure your patient has Transient Tachypnea of the Newborn? What are the typical findings for this disease?

Transient Tachypnea of the Newborn (TTN) is the most common cause of respiratory distress in the full-term infant, and frequently affects preterm infants. Affected patients may also be referred to as having retained fetal lung fluid. TTN results from a failure of the normal neonatal transition from in utero life to breathing air. Infants delivered via elective cesarean section are at substantially increased risk. It is a diagnosis of exclusion, made only after other causes of respiratory distress in the newborn have been excluded. The most common symptoms include:

  1. Tachypnea (respiratory rate >60 breaths/second in the newborn) developing in the first few hours of life

  2. Increased work of breathing, evidenced by nasal flaring, retractions, or grunting

  3. Hypoxemia (typically mild)

Neonatal Transition

At birth, the neonate must transition from placental to pulmonary gas exchange in what seems like a matter of minutes. However, at the time of spontaneous vaginal delivery, the process has been ongoing in the lung epithelium for several days.

During development, the lung is a secretory organ, and fetal lung fluid secretion is necessary for normal lung development and a contributor to amniotic fluid volume.

In the days prior to delivery, the lung epithelium slows its fluid production, gradually becoming an absorptive surface. This process is dependent on sodium channels (ENac) in the lung epithelium. The trigger for this switch is unknown, but it is well documented that activation of hormonal pathways (endogenous corticosteroids and catecholamines) occurs, driving the process. This results in an estimated 40% reduction of lung fluid volume prior to delivery, with another 20% removed during labor. The remainder of the fluid is resorbed by the vasculature and lymphatics after exposure to stretch and the relative hyperoxia of room air. Mechanical forces, such as vaginal squeeze, play a limited role in this process.

These pathways are developmentally regulated, so that prematurity increases the risk of delayed transition.

What are the consequences of delayed lung fluid clearance?

Retained fluid triggers a reflex arc through the respiratory center which results in tachypnea. Typically, these neonates have rapid, shallow breathing, often exceeding 100 breaths per minute. The work of breathing is generally not increased. Tachypnea continues until the fluid is cleared but is generally resolved in less than 72 hours after birth. Some infants can develop secondary pulmonary hypertension and can have a more involved clinical course, with hypoxia/respiratory distress requiring additional support.

What other disease/condition shares some of these symptoms?

There are numerous causes of respiratory distress in the newborn infant which require specific therapies and can be life-threatening. Although the clinical presentation is often more severe than seen in TTN, there is considerable overlap.

•pneumonia or sepsis

Bacterial and viral causes present in the neonate; common pathogens include Group B Streptococcus (GBS), Listeria, Escherichia coli and herpes simplex virus

Labor and delivery history may reveal maternal fever or fetal tachycardia, but also may be non-specific

Often accompanied by systemic signs and symptoms

Chest X-ray findings are also non-specific; lobar infiltrates are uncommon in neonates

•respiratory distress syndrome (RDS)

Surfactant deficiency or hyaline membrane disease

Primarily a disease of prematurity, but full-term infants can be affected

More pronounced respiratory distress with CO2 retention

Chest X-ray typically has a granular appearance, air bronchograms, and hypoaeration

•aspiration syndromes

Meconium aspiration, blood or amniotic fluid aspiration

Should be evident from clinical history and X-ray findings

Higher risk for pulmonary hypertension

•pneumothorax

Air leak can result from any cause of respiratory distress, including TTN, but can also be spontaneous or secondary to positive pressure support

Chest x-ray is diagnostic

•congenital malformations of the lung/thorax

Congenital diaphragmatic hernia (CDH), Congenital pulmonary airway malformation (CPAM), Bronchopulmonary sequestration, others

If distress occurs in the neonatal period, early surgery is often necessary.

Congenital chest wall abnormalities and pulmonary hypoplasia will often present in the neonatal period.

•pulmonary hypertension

Failure of fall in pulmonary vascular pressures causes right to left shunting and subsequent hypoxia that is often severe.

Often secondary to another cause of respiratory distress; may also be the primary problem

•congenital cardiac disease

Significant hypoxia with milder respiratory distress may occur, may also be systemically ill

Oxygenation will typically not improve or only minimally improve with supplemental oxygen.

Chest x-ray and EKG may help with diagnosis. Echocardiogram is diagnostic.

•metabolic derangements

Hypocalcemia and hypoglycemia

Metabolic acidosis of any cause can lead to tachypnea.

Cerebral causes of tachypnea will often have an alkalosis.

What caused this disease to develop at this time?

  • Clinical history is often suggestive of TTN. Many of the risk factors associated interrupt the normal process of labor or cause a relative dysmaturity in the infant. The diagnosis is most common in infants delivered by elective cesarean section in the absence of labor, although it can occur in those delivered after spontaneous onset of labor and those delivered vaginally. Premature infants (<36-6/7 weeks) and early term infants (37 to 38-6/7 weeks) are at increased risk. Other well-documented risk factors for the development of TTN include lack of rupture of membranes, male gender, maternal asthma, maternal diabetes, and maternal preeclampsia.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

  • An infant with mild tachypnea, no hypoxia, and who is systemically well may be observed initially. If tachypnea is accompanied by respiratory distress, persists longer than 6 hours, or is associated with other symptoms, then laboratory studies are indicated. A complete blood count (CBC) with differential and blood culture should be done to evaluate for an infectious etiology. Patients with TTN will typically have a normal CBC without increased white blood cell count or immature cells. Polycythemia can also cause respiratory distress and, if significant, may require an exchange transfusion.

  • If hypoxia develops requiring supplemental oxygen, an arterial blood gas (ABG) should be performed to assess oxygenation, ventilation, and evaluate for acidosis. Severe derangements in oxygenation and ventilation are unusual in TTN but can occur. This will also guide further therapy such as increased respiratory support or intubation.

  • For infants with prolonged tachypnea or risk factors (such as an infant of a diabetic mother), a chemistry and blood glucose should be performed.

  • There is no specific testing available that confirms the diagnosis of TTN. Rather, a suggestive history, normal laboratory evaluation, typical chest x-ray findings (see below), and ultimately a typical course with full recovery in 48 to 72 hours will confirm the diagnosis.

Would imaging studies be helpful? If so, which ones?

  • A chest x-ray (CXR) should be performed in infants suspected of having TTN. This is necessary to evaluate for other causes of tachypnea (e.g., anatomic abnormalities, pneumothorax, pneumonia). Typical findings may also help confirm the diagnosis of TTN. A single anterioposterior film is usually sufficient, although a lateral film may be helpful in identifying pneumomediastinum or pneumothorax. If the infant improves over the next 24 to 72 hours, repeat imaging is unnecessary.

  • This CXR (Figure 1) exhibits many of the findings typically seen in TTN, including increased perihilar markings, streaky opacities, hyperinflation with flattened diaphragms, and residual pleural fluid in the interlobar fissures (seen on the right).

Figure 1.

Typical chest x-ray in an infant with TTN

Confirming the diagnosis

  • There are no specific clinical algorithms for the diagnosis or treatment of TTN. Supportive care is the mainstay of treatment, with exclusion, as possible, of other causes of respiratory distress. Definitive diagnosis can only be made after other causes of tachypnea have been excluded and the patient has recovered fully.

If you are able to confirm that the patient has Transient Tachypnea of the Newborn, what treatment should be initiated?

Supportive Care

  • The mainstay of treatment for TTN is supportive care. Infants with isolated tachypnea without hypoxemia may not be able to feed and require IV hydration, even if no respiratory support is required. In general, if tachypnea has not improved by 6 hours of life or there are any symptoms of hypoglycemia, dextrose-containing IV fluids should be started. A preparation of 10% dextrose water without electrolytes is appropriate for a neonate on day of life zero, at a rate of 60 to 80mL/kg/day. Until the diagnosis of TTN has been clarified, infants often should be treated with antibiotics. Ampicillin, which covers group B streptoccus and listeria, is usually used in combination with a Gram-negative agent such as gentamicin.

  • The degree of respiratory support should be guided by the degree of illness. Tachypnea alone may not require specific treatment. Pulse oximetry should be used, and supplemental oxygen should be provided to keep saturations above 90% oxygen. This can be provided via nasal cannula or oxygen hood. High levels of oxygen supplementation, such as can be provided with a 100% oxygen hood, should be used with caution.

  • Infants with signs of distress other than tachypnea, such as grunting or retractions, or oxygen requirements >40% oxygen, should be evaluated with an arterial blood gas. Further support, such as nasal continuous positive airway pressure (NCPAP) or intubation, may be required. CXR should also be obtained on these infants.

  • Pneumothorax is a rare but serious potential complication of TTN. If the degree of distress is mild, this should be followed. Historically, nitrogen washout of trapped air by 100% oxygen hood has been used in an effort to speed the resolution of pneumothorax. This method has not been well studied. Given the known dangers of exposure to 100% oxygen, including free radical production and the development of atelectasis, it is now controversial. Large and symptomatic air leaks may require needle decompression or chest tube placement.

Specific Therapies

  • No specific therapies are considered standard of care for TTN. Small studies done administering Lasix (orally and intravenously) have shown increased weight loss but no effect on duration of symptoms or need for respiratory support. Knowledge of the role of catecholamines in lung fluid clearance led to recent pilot studies using inhaled epinephrine and the beta-2 agonist salbutamol. Epinephrine treatment did not change outcomes, but in the pilot study, inhaled salbutamol decreased maximum oxygen requirement and length of stay in a small group of patients. Further study is necessary.

What are the adverse effects associated with each treatment option?

In typical, mild-moderate cases of TTN where intravenous fluid supplementation and a limited amount of respiratory support are the only required therapies, serious adverse effects are rare. However these therapies do require NICU admission, separation from the family, and interruption of early bonding and feeding. Until the diagnosis becomes clear, infants are often treated with IV antibiotics, which ultimately are unnecessary. There is substantial financial cost to NICU admission, treatment, and a prolonged hospital stay that could be prevented because some cases of TTN are avoidable.

In very unusual cases, neonates with clinical history, laboratory work, and chest x-ray findings classic for transient tachypnea of the newborn will develop severe hypoxemia, necessitating substantial respiratory support, including intubation. Intubation carries a risk of trauma to the larynx and vocal cords and increases the risk of subsequent pneumonia. Exposure to a high fraction of inspired oxygen, even when necessary, can cause worsening lung inflammation, production of free radicals, and ultimately a higher risk of chronic lung disease.

Infants with this severe version of TTN are also at risk for delayed relaxation of the pulmonary vasculature, resulting in pulmonary hypertension. This may be treated with oxygen, inhaled nitric oxide, and ultimately extracorporeal membrane oxygenation (ECMO). ECMO requires anticoagulation, and the risk for a fatal intracranial hemorrhage in a newborn is approximately 5%.

What are the possible outcomes of Transient Tachypnea of the Newborn?

The prognosis for transient tachypnea of the newborn is generally excellent, with full recovery expected in three-quarters of affected infants by 48 hours of life. Hospital stays for infants treated for TTN are usually a day or two longer than those for healthy term infants, but infants with TTN are not expected to develop long-term sequelae from the illness. More rarely, tachypnea can be prolonged and require a lengthy hospital stay. Infants requiring prolonged respiratory support and nasogastric feedings often have poor oromotor skills, although this is usually temporary. Infants with TTN of unusual severity, which requires intubation, significant respiratory support, or even ECMO therapy, may have substantial residual lung disease throughout infancy and childhood.

What causes this disease and how frequent is it?

  • There is limited data about the exact incidence of transient tachypnea of the newborn, but it is estimated to affect about 5/1000 (0.5%) infants born at term. Incidence in those with risk factors is significantly higher. It is the most common etiology of respiratory distress in the term newborn and the second most common in the preterm newborn. Incidence at 34 weeks is estimated at 6.4%, with decreasing frequency with advancing gestational age. At 39 weeks gestation the estimated frequency of TTN is just 0.3% combined for all delivery types.

  • Elective cesarean section is a known, modifiable risk factor for TTN across all gestational ages. Even at 39 weeks the frequency of TTN in this population is estimated at 2.7%, a nearly ten-fold increase from the rate overall. Controversy exists over whether labor prior to cesarean delivery (secondary cesarean section) is protective. These infants have an incidence of respiratory morbidity intermediate between vaginally delivered infants and those delivered electively.

  • Epidemiologic data provides evidence for a genetic contribution to the development of transient tachypnea of the newborn. Familial clustering of unexplained cases of TTN is seen. A familial history of asthma, especially in the mother, is also associated with an increased risk for its development. Studied polymorphisms in the genes for surfactant protein B (SPB) and epithelial sodium channels (ENac) were not found to be associated, while a loss of function beta-adrenergic receptor polymorphism was seen in increasing frequency in term infants that had been diagnosed with TTN. Genetic studies are limited and currently only available on an experimental basis.

How do these pathogens/genes/exposures cause the disease?

  • The main pathophysiologic factor associated with TTN is understood to be delayed resorbance of fetal lung fluid. The hormonal changes that occur before and during spontaneous labor plan a key role in this process. Increased steroid hormones and circulating catecholamines result in increased gene transcription and decreased degradation of pivotal epithelial sodium channels (ENac), resorption of fetal lung fluid, and preparation for breathing. Practices that interfere with spontaneous labor, such as elective cesarean section, will delay this transition.

  • Another causative factor in delayed clearance of fetal lung fluid is prematurity.The systems by which fluid clearance occurs are developmentally regulated, such that the premature infant is not as well prepared to respond to labor. The supply of ENac channels, which play a critical role in fluid resorption, is lower in premature infants and must be increased over time. Causes of lung dysmaturity in term infants, such as maternal diabetes and congenital diaphragmatic hernia, are also associated with a delay in lung fluid clearance.

  • Genetic contributions also likely play a large role in which infants, born after similar circumstances, are clinically symptomatic and diagnosed with TTN. Knowledge thus far is limited. Abnormalities in any of the genes involved in the onset of labor, preparation of the infant for delivery, or neonatal transition could easily lead to the development of TTN. Since labor itself is poorly understood, many of these genes are not yet known.

Other clinical manifestations that might help with diagnosis and management

Some infants experience tachypnea interspersed with episodes of apnea. Respiratory muscle fatigue has been proposed as a possible cause, but studies supporting such a connection are generally lacking. Infants with TTN may have trouble initiating oral feeds and are at a higher risk for related complications such as hypoglycemia and exaggerated physiologic jaundice.

What complications might you expect from the disease or treatment of the disease?

Since the disease is often self-limited and benign, no treatment is recommended. Risks associated with high concentrations of oxygen and positive pressure ventilation are relatively rare but can cause significant morbidity.

Are additional laboratory studies available; even some that are not widely available?

Research studies are periodically conducted involving genetic testing or lung chemistry in affected infants, including surfactant production. None of this testing is currently useful clinically.

How can Transient Tachypnea of the Newborn be prevented?

One of the keys in the prevention of TTN is limiting cesarean section whenever possible, and planning elective cesarean deliveries, when deemed necessary, at or after 39 weeks gestation. Retrospective studies have clearly shown that all cesarean deliveries are associated with an increased rate of neonatal respiratory morbidities. This is not completely attenuated by the presence of labor prior to delivery. When considering a primary cesarean section, multiple factors affecting maternal and fetal health must be taken into consideration.

The role of prenatal betamethasone, well known to improve morbidity due to respiratory distress syndrome in premature infants, has been evaluated as a potential treatment for TTN, specifically that which occurs following elective cesarean. Prenatal steroid administration to infants delivered in the late preterm period (34 to 36-6/7 weeks) has not been shown to decrease the risk of respiratory distress syndrome (RDS), although most studies were not powered to evaluate a reduction in TTN. One randomized trial has been conducted in the term population. Betamethasone prior to elective cesarean delivery was shown to decrease the risk of NICU admission for respiratory distress, but not the overall rate of NICU admission. Such therapy may eventually become standard practice, but more studies need to be conducted. Another large study sponsored by the National Institutes of Health, which will evaluate the role of antenatal betamethasone in late preterm gestations, is underway.

What is the evidence?

Epidemiology

Tita, AT, Landon, MB, Spong, CY. "Timing of elective repeat cesarean delivery at term and neonatal outcomes". N Engl J Med. vol. 360. 2009. pp. 111-20.

• This is a cohort study of neonatal morbidities in 13,528 full term infants born after elective repeat cesarean section. Rates of all neonatal morbidities, including respiratory complications, TTN, and NICU admission, were significantly increased in infants born at 37 and 38 weeks compared to a nadir at 39 to 40 weeks. Rates of TTN were 4.8% at 37 weeks, 3.9% at 38 weeks, and 2.7% at 39 weeks (p for trend <0.001). These findings supported the ACOG recommendation advising against purely elective cesarean sections prior to 39 weeks gestation.

Hibbard, JU, Wilkins, I, Sun, L. "Respiratory morbidity in late preterm births". JAMA. vol. 304. 2010. pp. 419-25.

•Retrospective data collection was performed on 233,844 deliveries, with 19,334 of them late preterm (LPT) infants (34 to 36-6/7 weeks) which were compared with term infants. Rates of maternal morbidities and cesarean section without labor were higher in the late preterms. Respiratory complications were frequent, most commonly RDS (respiratory distress syndrome) followed by TTN, which had an OR of 14.7 (11.7-18.4) at 34 weeks, 11.1 (9.1-13.6) at 35 weeks, and 6.1 (5.1-7.4) at 36 weeks compared with infants born at 39 to 40 weeks (all delivery methods).

Tutdibi, E, Gries, K, Bücheler, M. "Impact of labor on outcomes in transient tachypnea of the newborn: population-based study". Pediatrics. vol. 125. 2010. pp. e577-83.

•Data collected from perinatal and neonatal databases identified 1423 full term infants (>37 weeks) diagnosed as having TTN, an overall incidence of 5.9/1000 in the population. The effect of the presence or absence of labor was studied by comparing infants born after primary cesarean delivery (CD) with those born vaginally or by secondary section after labor. The risk of TTN was significantly increased in the CD group; this risk was further increased in the younger infants when compared to those delivered after 40 weeks gestation. The CD infants also had increased severity of TTN as evidenced by longer oxygen requirement (p < 0.02) and increased rates of mechanical ventilation (p <0.002).

Silasi, M, Coonrod, DV, Kim, M, Drachman, D. "Transient tachypnea of the newborn: is labor prior to cesarean delivery protective?". Am J Perinatol. vol. 27. 2010. pp. 797-802.

•A case control study using birth records was performed on 1600 infants, gestational age 35 to 41 weeks , 800 diagnosed with TTN. Cesarean delivery was associated with an increased risk of TTN [OR 2.58 (1.99 -3.36)], but this was not offset by the presence of labor prior to cesarean section.

Treatment

Stutchfield, P, Whitaker, R, Russell, I. "Antenatal betamethasone and incidence of neonatal respiratory distress after elective caesarean section: pragmatic randomized trial". BMJ. vol. 331. 2005. pp. 662.

•This randomized non-blinded trial compared the outcomes for infants delivered via elective cesarean section (after 37 weeks) who received prenatal betamethasone with a placebo group that did not. The average gestational age at delivery was 38-3/7 weeks. Betamethasone reduced the rate of NICU admission for respiratory complications (p=0.02), but the study was underpowered to detect differences in specific diagnoses such as TTN and RDS. However, overall rate of NICU admission for all causes was not different between the two groups. Morbidities were more common in both groups at 37 and 38 weeks compared with 39 weeks.

Armangil, D, Yurdakök, M, Korkmaz, A. "Inhaled beta-2 agonist salbutamol for the treatment of transient tachypnea of the newborn". J Pediatr. vol. 159. 2011. pp. 398-403.

•This pilot study randomized 54 infants 34-39 weeks to treatment with a single dose of inhaled salbutamol or saline placebo. There were 32 infants who received the treatment and were evaluated four hours later. Statistically significant changes in respiratory rate and fraction of inspired oxygen were found, as well as a shorter duration of hospital stay in the treatment group. No significant side effects were seen in this pilot study, and the authors concluded that larger studies are warranted.

Ongoing controversies regarding etiology, diagnosis, treatment

First, there is ongoing debate about the high rate of cesarean sections, both primary and repeat, which have undoubtedly increased the incidence of TTN. Proponents of operative delivery believe that these interventions have decreased uterine ruptures, stillbirths, and birth asphyxia. However, the absolute number of these arguably serious complications is low compared to the much more commonly reported complications like TTN. It is not clear where the perfect balance sits for cesarean sections and induced deliveries.

Second, many centers offer early and aggressive oxygen/positive pressure respiratory support to symptomatic newborns. High oxygen concentrations administered in hoods/tents can lead to progressive atelectasis because of nitrogen washout from alveolar spaces. There is additional risk of oxygen toxicity from free radicals. Atelectasis can be prevented by use of CPAP when using high oxygen concentrations (>40%) but carries its own risk of air leaks.

Finally, basic science studies suggest that antenatal steroids should enhance lung fluid clearance and facilitate neonatal transition, particularly in situations where the endogenous steroid surge has not occurred (as in elective cesarean sections). More studies will be needed to assess the long-term risks of exposing a large number of mothers and their fetuses to steroids before such a treatment can be recommended.

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