The seminal complication of the preterm newborn is respiratory distress syndrome (RDS). This results from immature lungs that are unable to sustain necessary oxygenation. Resulting hypoxia is an underlying associated cause of neurological damage such as cerebral palsy. In addition, hyperoxia, a side effect of RDS treatment, contributes to morbidities such as bronchopulmonary dysplasia, pulmonary hypertension, necrotizing enterocolitis, periventricular leukomalacia, and retinopathy of prematurity.
To provide blood gas exchange immediately following delivery, the lungs must rapidly fill with air while being cleared of fluid. Concurrently, pulmonary arterial blood flow must rise remarkably. Although some of the fluid is expressed as the chest is compressed during vaginal delivery, most is absorbed through the pulmonary lymphatics via complex mechanisms described in Chapter 32 (Transition to Air Breathing). Sufficient surfactant, synthesized by type II pneumocytes, is essential to stabilize the air-expanded alveoli. It lowers surface tension and thereby prevents lung collapse during expiration (Chap. 7, Respiratory System). If surfactant is inadequate, hyaline membranes form in the distal bronchioles and alveoli, and RDS develops. Although respiratory distress syndrome is generally a disease of preterm neonates, it does develop in term newborns, especially with sepsis or meconium aspiration. In these cases, surfactant can be inactivated by inflammation and/or presence of meconium (Chap. 33, Respiratory Distress).
With inadequate surfactant, alveoli are unstable, and low pressures cause collapse at end expiration. Pneumocyte nutrition is compromised by hypoxia and systemic hypotension. Partial persistence of the fetal circulation may lead to pulmonary hypertension and a relative right-to-left shunt. Eventually, alveolar cells undergo ischemic necrosis. When oxygen therapy is initiated, the pulmonary vascular bed dilates, and the shunt reverses. Protein-filled fluid leaks into the alveolar ducts, and the cells lining the ducts slough. Hyaline membranes composed of fibrin-rich protein and cellular debris line the dilated alveoli and terminal bronchioles. The epithelium underlying the membrane becomes necrotic. At autopsy, with hematoxylin-eosin staining of lung tissue, these membranes appear amorphous and eosinophilic, like hyaline cartilage. Because of this, respiratory distress syndrome is also termed hyaline membrane disease.
In typical RDS, tachypnea develops, the chest wall retracts, and expiration is accompanied by nostril flaring and by grunting—in an attempt to provide a positive end-expiratory pressure to prevent lung collapse. Shunting of blood through nonventilated lung contributes to hypoxemia and to metabolic and respiratory acidosis. Poor peripheral circulation and systemic hypotension may be evident. The chest radiograph shows a diffuse reticulogranular infiltrate and an air-filled tracheobronchial tree—air bronchogram.
As discussed further in Chapter 33 Respiratory Distress, respiratory insufficiency can also be caused by sepsis, pneumonia, meconium aspiration, pneumothorax, persistent fetal circulation, heart failure, and malformations involving thoracic structures, such as diaphragmatic hernia. Common mutations in surfactant protein production and the phospholipid transporter (ABCA3) contribute to RDS (Beers, 2017; Tredano, 2003; Wert, 2009).
An important factor influencing survival is neonatal intensive care. Although hypoxemia prompts supplemental oxygen, excess oxygen can damage the pulmonary epithelium, retina, and other immature tissues. Despite this, advances in mechanical ventilation technology have improved neonatal survival rates. For example, continuous positive airway pressure (CPAP) prevents the collapse of unstable alveoli. This allows high inspired-oxygen concentrations to be reduced, thereby minimizing its toxicity. In an attempt to minimize the need for tracheal intubation and intermittent positive-pressure ventilation, CPAP has been studied in well-designed multicenter trials (Morley, 2008; SUPPORT Study Group, 2010b). An initial CPAP strategy with subsequent selective surfactant use is a beneficial alternative to immediate intubation and surfactant for many neonates of extremely early gestational age (American Academy of Pediatrics, 2014).
Mechanical ventilation has undoubtedly improved survival rates but is an important factor in the genesis of chronic lung disease of prematurity—bronchopulmonary dysplasia (BPD). Namely, mechanical ventilation places a newborn at risk for barotrauma and volutrauma. Moreover, hyperoxia can create reactive oxygen species that trigger inflammation. Infection can also be contributory. In affected newborns, alveolar and pulmonary vascular development is disrupted and leads to hypoxia, hypercarbia, and chronic oxygen dependence (Davidson, 2017; Kair, 2012).
As prevention, high-frequency oscillatory ventilation has been evaluated. However, benefits and risks varied considerably between studies (Cools, 2015).
Treatment of the ventilator-dependent neonate with glucocorticoids was also used previously to prevent BPD. The American Academy of Pediatrics now recommends against routine steroid use because of limited benefits and greater rates of impaired motor and cognitive function and school performance in exposed neonates (Doyle, 2014a,b; Watterberg, 2010).
In other efforts for BPD prevention, early animal studies demonstrated significant improvements in lung function with weeks of inhaled nitric oxide (McCurnin, 2005). Despite initial enthusiasm, clinical trials failed to demonstrate a consistent benefit. A National Institutes of Health (NIH) consensus statement and the American Academy of Pediatrics (2014) concluded that the available data do not support its use to prevent or treat BPD (Cole, 2011).
Caffeine has been used widely to treat apnea of prematurity, but it also has bronchodilatory effects. One large randomized trial of caffeine versus placebo showed lower BPD rates, improved neurodevelopmental outcomes during early childhood, and good evidence of safety up to 11 years (Schmidt, 2006, 2012, 2017). This therapy is now widely used for newborns weighing ≤1250 g.
The antioxidant vitamin A is necessary for normal lung growth and the integrity of respiratory tract epithelial cells. Preterm newborns have low vitamin A levels at birth, and this has been associated with a greater risk of developing BPD. Randomized trials support the use of vitamin A to achieve a modest reduction in BPD rates for very-low-birthweight neonates weighing <1500 g (Darlow, 2016).
Surfactant Prophylaxis and Rescue
Exogenous surfactant products are delivered via endotracheal tube to help prevent RDS. They contain biological or animal surfactants such as bovine—Survanta, calf—Infasurf, or porcine—Curosurf. Synthetic surfactants such as first-generation Exosurf and second-generation Surfaxin R are equivalent but not superior to animal-derived surfactant (Moya, 2007). In a Cochrane review, Ardell and coworkers (2015) found that animal-derived surfactants led to better outcomes than synthetic surfactants, which do not contain important surfactant proteins. There are currently no synthetic surfactants available.
Surfactant replacement was established decades ago as an effective and safe therapy for RDS. Treatment reduces rates of mortality and pneumothorax and improves survival without BPD (Polin, 2014). It has been used for prophylaxis of preterm, at-risk newborns and for rescue of those with established disease. Given together, antenatal corticosteroids and surfactant result in an even greater reduction in the overall death rate. However, randomized trials indicate that in populations with high use of antenatal steroids and routine use of CPAP in the delivery room, prophylactant surfactant is no longer beneficial and is associated with more risk of death or BPD (Rojas-Reyes, 2012; Sardesai, 2017). Exploration of different, less invasive ways to deliver rescue surfactant to spontaneously breathing preterm neonates is currently underway. Potential routes include surfactant application into the pharynx, surfactant nebulization, or application via laryngeal mask or via a thin catheter placed in the trachea (Kribs, 2016).
The NIH (1994, 2000) has concluded that a single course of antenatal corticosteroid therapy reduces RDS and intraventricular hemorrhage rates in preterm neonates born between 24 and 34 weeks’ gestation (Cerebral Palsy). The American College of Obstetricians and Gynecologists (2016a) considers all women at risk for preterm birth in this gestational-age range to be potential candidates for therapy. It also may be considered for pregnant women starting at 23 weeks’ gestation who are at risk of preterm delivery within 7 days. This is discussed further is Chapter 42 (Corticosteroids for Fetal Lung Maturation). More recently, administration of antenatal corticosteroids to women at risk for late-preterm delivery (34 to 36 weeks’ gestation) was found to significantly reduce the rate of neonatal respiratory complications (Gyamfi-Bannerman, 2016).
Amniocentesis to Assess Fetal Lung Maturity
In some instances, when gestational age is uncertain, knowledge of fetal lung maturity may influence plans for delivery. One example is the woman with a prior classical cesarean delivery in whom repeat operation is planned and gestational age cannot be confirmed. Several tests are used to ensure fetal pulmonary maturity by analysis of amnionic fluid obtained by sonographically guided amniocentesis. At Parkland Hospital, we still find an occasional indication for such testing, however, the American College of Obstetricians and Gynecologists (2017a,b) counsels against its use in most of these cases. Instead the College recommends late-term delivery at “41 weeks’ gestation” using the best clinical estimate of gestational age (Chap. 10 Gestational Age Assessment).
If amniocentesis is elected, fluid acquisition is similar to that described for second-trimester amniocentesis (Chap. 14, Technique). Complications requiring urgent delivery are rare (Zalud, 2008). Following analysis, the probability of RDS developing in a given newborn depends on the test used and fetal gestational age. Importantly, administration of corticosteroids to induce pulmonary maturation has variable effects on some of these tests. Varner and colleagues (2013) have provided a review of testing options.
Of biochemical tests, the labor-intensive lecithin-sphingomyelin (L/S) ratio for many years was the gold-standard test. Dipalmitoylphosphatidylcholine (DPPC), that is, lecithin, and sphingomyelin are surfactant components. Before 34 weeks, both are present in amnionic fluid in similar concentrations. At 32 to 34 weeks, the concentration of lecithin relative to sphingomyelin begins to rise (Fig. 34-1). The risk of neonatal RDS is slight whenever the concentration of lecithin is at least twice that of sphingomyelin—L/S ratio >2 (Gluck, 1971). Previously, RDS was thought to develop despite an L/S ratio >2 in newborns of women with diabetes. Some recommend that phosphatidylglycerol, another surfactant phospholipid, be documented in amnionic fluid of these women. Based on current evidence, it is unclear if either diabetes, per se, or its level of control causes false-positive phospholipid test results for fetal lung maturity (De Luca, 2009).
Changes in mean concentrations of lecithin and sphingomyelin in amnionic fluid during gestation in normal pregnancy. (Modified with permission from Gluck L, Kulovich MV: Lecithin-sphingomyelin ratios in amniotic fluid in normal and abnormal pregnancy, Am J Obstet Gynecol. 1973 Feb 15;115(4):539–546.)
Of biophysical tests, the fluorescence polarization test is an automated assay that measures the surfactant-to-albumin ratio in uncentrifuged amnionic fluid and gives results in less than an hour. Investigators found the TDx-FLM to be equal or superior to the L/S ratio, foam stability index, or phosphatidylglycerol assessment. This included testing in diabetic pregnancies (Karcher, 2005; Varner, 2013). The modified TDx-FLM II is used by many hospitals as their primary test of pulmonary maturity. Thresholds vary by gestational age (Bennasar, 2009). The foam stability or shake test relies on the ability of surfactant in amnionic fluid, when mixed appropriately with ethanol, to generate stable foam at the air–liquid interface (Clements, 1972). Problems include errors caused by slight contamination and frequent false-negative test results. Of other tests, the Lumadex-FSI test, fluorescent polarization (microviscometry), and amnionic fluid absorbance at 650-nm wavelength have all been used with variable success.
The lamellar body count is a rapid, simple, and accurate method of assessing fetal lung maturity and is comparable to TDx-FLM and L/S ratio accuracy (Karcher, 2005; Varner, 2013).