Transient Tachypnea of the Newborn

It can be challenging to diagnose and provide optimal treatment for transient tachypnea of the newborn.After completing this article, readers should be able to:Fetal lungs are filled with liquid that is crucial for normal lung growth. After birth, this fetal alveolar fluid is cleared through pulmonary epithelial, vascular, and lymphatic channels. A delay in fluid clearance leads to ineffective gas exchange and results in respiratory distress. This impermanent condition of retained fetal lung fluid is known as transient tachypnea of the newborn (TTN). (1)(2)TTN is one of the leading causes of neonatal respiratory distress and is therefore an important diagnosis to consider, identify correctly, and manage. (3) It is generally a benign, self-limited condition that presents shortly after birth and occurs in infants of any gestational age. Diagnosis of TTN is based on an infant’s clinical presentation, physical examination findings, and classic chest radiographic findings. The management consists of supportive care, with symptoms generally resolving by 24 to 72 hours of age.As early as 6 weeks of gestation, the fetal lung epithelium begins to secrete alveolar fluid at 2 mL/kg per hour, increasing to a rate of 5 mL/kg per hour at term. (4) This liquid is crucial for normal lung growth and contributes to the volume of amniotic fluid that surrounds the fetus. A few days before the onset of spontaneous vaginal delivery, fluid production decreases. (5) With the onset of labor, maternal hormones such as epinephrine and glucocorticoids stimulate the fetal lungs to begin absorption of alveolar fluid through activation of an amiloride-sensitive epithelial sodium channel (ENaC). (4) Animal studies of α-ENaC knockout mice have shown that when sodium transport is inactivated, alveolar fluid retention occurs, which leads to respiratory distress and death. (6)The clearance of fetal lung fluid begins with passive sodium transport across ENaC proteins, which are found on the apical membrane of alveolar type II pneumocytes. After sodium enters the type II cell, it is actively transported into the pulmonary interstitium via a basolateral sodium-potassium (Na+/K+) ATPase pump. This creates an osmotic gradient that allows chloride and water to follow and be absorbed into the pulmonary circulation and lymphatics (Fig 1). (1)(7) It is through this mechanism that most of the fetal lung fluid is cleared. Starling forces and the thoracic “squeeze” through the birth canal contribute minimally toward fluid elimination. (2)TTN is one of the most common causes of neonatal respiratory distress. TTN occurs in ∼10% of infants born between 33 and 34 weeks of gestation, ∼5% of infants delivered at 35 to 36 weeks, and fewer than 1% of all term infants. (8)(9) Generally the rate of respiratory morbidity is inversely proportional to gestational age. In 2013, the American College of Obstetricians and Gynecologists published guidelines recommending avoidance of nonmedically indicated vaginal or cesarean deliveries at less than 39 weeks of gestation. (10)(11)Recently, data from the Antenatal Late Preterm Steroids (ALPS) Trial examined whether betamethasone administration in pregnant women at risk for late preterm delivery would affect neonatal respiratory morbidity. The ALPS Trial was a multicenter, double-blind, randomized controlled trial that included 2,831 infants born between 34 07 and 36 67 weeks’ gestation whose mothers received antenatal corticosteroids. The investigators found that late preterm neonates whose mothers received betamethasone had a decreased incidence of TTN and required less continuous positive airway pressure (CPAP) and fraction of inspired oxygen (FiO2). (12) Administration of corticosteroids before delivery may improve TTN symptoms through induction of ENaC, which is involved in fetal fluid absorption. (13) How this new practice may affect the incidence of other neonatal morbidities is unclear.There are well-established risk factors that may contribute to the development of TTN (Table 1). These include male sex, birth asphyxia, maternal gestational diabetes, and cesarean section without labor or delivery before 39 weeks of gestation. (14)(15) Preterm infants are at an increased risk for TTN, which is inversely proportional to their degree of prematurity. Small- and large-for-gestational age infants are also at an increased risk of developing TTN. Although maternal asthma is a known risk factor, the mechanism is not well defined. (16)Infants with TTN generally present within the first few minutes to hours after birth. They have signs of respiratory distress such as tachypnea (respiratory rate >60 breaths/min), nasal flaring, grunting, and intercostal, subcostal, and/or suprasternal retractions. On auscultation, breath sounds may be diminished, crackles may be appreciated, or lung fields may be clear. Tachycardia may often be associated. Newborns with TTN may also have cyanosis and need supplemental oxygen, but usually no more than an FiO2 of 0.40.If signs of respiratory distress resolve within the first few hours after birth, this may be due to a brief delay in lung fluid absorption, and is commonly referred to as “delayed transition.” However, if respiratory distress persists beyond a clinically acceptable period (eg, 2–6 hours) and continued support is needed, then all causes of neonatal respiratory distress should be considered, including TTN.TTN is a diagnosis of exclusion, thus other causes of neonatal respiratory distress presenting soon after birth must be excluded (Table 2). The diagnosis is made based on an infant’s clinical presentation, physical examination findings, and chest radiography findings. If symptoms persist beyond 72 hours after birth, alternative diagnoses to TTN must be examined. TTN cannot be confirmed until symptoms resolve completely.Radiographic findings in TTN can include fluid in the interlobar fissure, bilateral alveolar and interstitial edema, prominent pulmonary vascular pattern with increased perihilar markings, and lung hyperinflation (Figs 2–4).On initial chest radiography in a newborn with TTN, bilateral patchy alveolar edema may be difficult to differentiate from neonatal pneumonia. However, radiographic findings that clear after 24 hours are more consistent with TTN (Fig 5). In addition, preterm infants can have radiographic evidence of retained fetal lung fluid and surfactant deficiency simultaneously.Based on a newborn’s clinical condition and infectious risk factors, laboratory tests may need to be performed. Blood tests to consider include a complete blood cell (CBC) count, C-reactive protein (CRP), arterial blood gases (ABG), lactate, and blood culture. In addition, empiric antibiotic therapy for early neonatal sepsis (eg, ampicillin and gentamicin) should be considered, because TTN may be difficult to clinically distinguish from neonatal sepsis or pneumonia.ABG analysis may demonstrate mild hypoxemia and hypocapnia due to tachypnea. If hypercapnia is present, it may be a sign of fatigue or other complication such as an air leak. If persistent tachypnea is present in the setting of lethargy and metabolic acidosis, an ammonia level will help evaluate for an inborn error of metabolism. In the presence of hypoxia, pre- and postductal saturations will help to evaluate for differential cyanosis. If differential cyanosis is uncovered, then an echocardiogram should be obtained to rule out congenital heart disease or persistent pulmonary hypertension of the newborn. Echocardiography should also be performed to rule out congenital heart disease in neonates with presumed TTN who have tachypnea for more than 4 to 5 days. A reasonable approach in the care of a term neonate with respiratory distress is the “rule of 2 hours.”(17) Two hours after the onset of neonatal respiratory distress, if an infant’s condition has not improved or has worsened, if the infant is requiring FiO2 greater than 0.4, or chest radiography findings are abnormal, practitioners should consider transferring the infant to a center that can provide a higher level of neonatal care.Given that TTN is a self-limited condition, the mainstay of treatment is supportive care. Routine NICU support should be provided, including continuous cardiopulmonary monitoring, maintenance of a neutral thermal environment, optimizing fluid balance, checking blood glucose levels, and observation for signs of infection.Securing intravenous (IV) access should be considered in neonates with suspected TTN, given the high likelihood of requiring IV fluids or IV nutrition, because many infants with tachypnea and respiratory distress will likely have a delay in advancement of enteral feeding. If an infection is highly suspected, the infant will also require IV access for antibiotic therapy. Generally, an arterial line is not required for the management of TTN. If frequent ABG measurements are required or the infant needs arterial monitoring for hypotension, other causes should be considered.Neonates with TTN may require noninvasive respiratory support (eg, nasal cannula, nasal CPAP) and may need supplemental oxygen to maintain normal oxygen saturation levels. If a newborn is requiring FiO2 greater than 0.40 or endotracheal intubation, there is increased likelihood of another cause of the child’s distress. The clinical picture should be reevaluated, presence of differential cyanosis assessed, and additional testing considered. This includes repeat laboratory tests, such as a CBC count, CRP, ABG, lactate, ammonia level, and imaging, such as chest radiography and/or echocardiography.An infant’s respiratory condition is the determining factor for receiving enteral or IV nutrition. Often the clinical status and degree of tachypnea make it unsafe for an infant to receive oral feeds and instead the infant can receive nutrition via gavage feeding, IV solution, or a combination of both. When an IV solution (eg, dextrose-containing electrolyte fluid, peripheral or total parenteral nutrition) is administered, electrolytes should be monitored closely. Central line placement may be indicated to meet nutritional or electrolyte requirements.A single-center, randomized, controlled trial involving 67 neonates demonstrated a possible role for fluid restriction in newborns with severe TTN, defined as infants requiring respiratory support for 48 hours or more. In the first 24 hours after birth, total fluid intake was restricted to 40 mL/kg per day in term infants and 60 mL/kg per day in preterm infants. In both groups, total fluids were advanced by 20 mL/kg per day. Fluid restriction decreased the duration of respiratory support, decreased the cost of hospitalization, and did not cause dehydration. (18) However, this is not currently considered standard practice and further multicenter, randomized, controlled trials are needed.Currently, strong data to support the routine use of medications in the treatment of TTN are lacking. Medications studied include diuretic therapy, inhaled racemic epinephrine, and inhaled β2-agonists. A recent systematic review analyzed the usefulness of routine diuretic therapy for TTN and concluded that neither oral nor IV furosemide provided any benefit by improving symptoms or reducing duration of hospitalization. (19) A small study of 20 newborns looked at the safety and efficacy of inhaled racemic epinephrine as a potential treatment for TTN. (20) The authors did not observe issues with medication safety, but the number of study patients was too small to determine efficacy or make any generalizable conclusions. Last, the inhaled β2-agonist salbutamol has been studied and may have promise as a possible treatment option to improve respiratory symptoms associated with TTN and decrease hospital length of stay. (21)(22) Nevertheless, recent systematic reviews have concluded that more evidence is needed to confirm the efficacy and safety of inhaled epinephrine and β2-agonists in the treatment of TTN. (23)(24) Further studies need to be conducted on a larger scale; therefore, these treatments are not currently recommended as standard therapy for TTN.Studies have demonstrated an association between TTN and subsequent development of asthma, suggesting an underlying genetic predisposition. (25)(26) The risk of asthma is further increased if a neonate is delivered via cesarean section. (27)(28) More studies need to be conducted to make definitive conclusions about a possible causative link between TTN and asthma. In addition, there have been reports of “malignant TTN,” in which affected children develop persistent pulmonary hypertension of the newborn. (29) Some suggest that early use of distending pressure (eg, nasal CPAP) may mitigate the course of this severe form of TTN. Nevertheless, the overall prognosis is generally excellent in neonates with TTN. In the vast majority of infants, the symptoms will resolve within 48 hours. Rarely, tachypnea may last for a week or more.