What is the role of lung surfactant in fetal development, particularly in preventing respiratory distress syndrome (RDS) in preterm infants?

Lung Surfactant in Fetal Development and Prevention of Respiratory Distress Syndrome

Lung surfactant is a critical substance that reduces alveolar surface tension and prevents alveolar collapse during ventilation; its deficiency in preterm infants causes respiratory distress syndrome (RDS), which is effectively treated with exogenous surfactant replacement therapy that reduces mortality by 30-40% and significantly decreases pneumothorax and pulmonary interstitial emphysema. 1

Physiological Role of Surfactant in Fetal Lung Development

Endogenous pulmonary surfactant reduces surface tension at the air-liquid interface of the alveoli during ventilation and stabilizes the alveoli against collapse at resting transpulmonary pressures. 2 The surfactant system consists of 99% polar lipids (mainly phospholipids including phosphatidylcholine) and 1% hydrophobic low molecular weight surfactant-associated proteins (SP-B and SP-C). 2

• Surfactant production is a key developmental milestone in fetal lung maturation, with adequate amounts necessary to prevent RDS after birth. 3
• The lack of adequate surfactant in preterm infants results in RDS characterized by poor lung expansion, inadequate gas exchange, and progressive alveolar collapse (atelectasis). 2
• Surfactant components also silence inflammatory responses, bind and destroy airborne microbes, and facilitate phagocytosis by alveolar macrophages. 4

Surfactant Deficiency and Respiratory Distress Syndrome

Respiratory failure secondary to surfactant deficiency is a major cause of morbidity and mortality in preterm infants, particularly those born before 30 weeks' gestation or with birth weight <1250 g. 1

• RDS occurs most commonly in preterm infants who have not yet developed adequate surfactant production capacity. 1
• The surfactant system protects both the fetus and newborn by ameliorating inflammatory responses that are harmful during the perinatal period. 4

Surfactant Replacement Therapy: Evidence and Outcomes

Surfactant replacement therapy substantially reduces mortality and respiratory morbidity in preterm infants with RDS, with animal-derived surfactants showing mortality reduction (RR 0.60-0.68) and synthetic surfactants showing similar benefits (RR 0.70-0.73). 1, 5

Mortality and Major Complications

• Surfactant therapy reduces neonatal mortality by 32-40% compared to no treatment (animal-derived prophylactic RR 0.60,95% CI 0.47-0.77; rescue RR 0.68,95% CI 0.57-0.82). 1
• Pneumothorax incidence is reduced by 58-60% with animal-derived surfactant (prophylactic RR 0.40,95% CI 0.29-0.54; rescue RR 0.42,95% CI 0.34-0.52). 1
• Pulmonary interstitial emphysema is reduced by 54-55% (prophylactic RR 0.46,95% CI 0.36-0.59; rescue RR 0.45,95% CI 0.37-0.55). 1
• The combined outcome of bronchopulmonary dysplasia (BPD) or death is reduced by 17-20% with animal-derived surfactant (prophylactic RR 0.80,95% CI 0.72-0.88; rescue RR 0.83,95% CI 0.77-0.90). 1

Timing of Administration

Early rescue surfactant (within 1-2 hours of birth) is superior to late rescue surfactant (≥2 hours after birth) in reducing adverse respiratory outcomes in infants <30 weeks' gestation. 5, 6

• Surfactant should be administered as soon as possible after intubation in infants with RDS, regardless of gestational age or antenatal steroid exposure. 5, 6
• For extremely preterm infants at high risk of RDS without antenatal steroid exposure, prophylactic surfactant (within 10-30 minutes after birth) may be beneficial. 5
• However, when continuous positive airway pressure (CPAP) is routinely used for stabilization, the benefits of prophylactic surfactant on mortality (RR 0.89,95% CI 0.76-1.04) and air leak are no longer demonstrated, and infants receiving prophylactic surfactant had higher incidence of BPD or death (RR 1.12,95% CI 1.02-1.24). 1

Synergy with Antenatal Corticosteroids

Antenatal steroids and postnatal surfactant replacement independently and additively reduce mortality, severity of RDS, and air leaks in preterm infants. 1, 5, 7

• Antenatal steroids stimulate structural maturation and surfactant synthesis in the fetal lung. 1
• Betamethasone administration (12 mg intramuscularly, two doses 24 hours apart) substantially reduces the need for respiratory support (RR 0.80) and severe respiratory morbidity (RR 0.67). 7
• Antenatal steroids may reduce the need for prophylactic and early rescue surfactant replacement in infants born after 27-28 weeks' gestation. 1, 5
• The combination provides an additive effect, with antenatal steroids also reducing intraventricular hemorrhage risk (RR 0.60,95% CI 0.43-0.83). 1

Clinical Application and Management

Preterm and term infants receiving surfactant-replacement therapy should be managed in facilities with technical and clinical expertise to administer surfactant and provide multisystem support, as respiratory insufficiency may be a component of multiorgan dysfunction. 1

• Both animal-derived (natural) and synthetic surfactants decrease respiratory morbidity and mortality in preterm infants with surfactant deficiency. 5
• CUROSURF (poractant alfa) is FDA-approved for rescue treatment of RDS in premature infants, including reduction of mortality and pneumothoraces. 2
• The initial dose of CUROSURF is 2.5 mL/kg (200 mg/kg), with up to two additional 1.25 mL/kg doses if needed. 2
• Newer synthetic surfactants with surfactant protein-like activity show promise as treatments for surfactant deficiency disorders. 1, 5

Long-Term Outcomes and Safety

Surfactant replacement increases survival rates without an increase in risk of disabilities, resulting in an absolute increase in the number of preterm infants who survive both with and without disabilities. 1

• Follow-up data for weight, length, persistent respiratory symptoms, cerebral palsy, visual impairment, and auditory impairment show similar outcomes between surfactant-treated and control groups. 2
• The incidence of BPD is lower in treated infants born at ≥30 weeks' gestation compared with untreated infants. 1, 5
• Treatment with exogenous surfactant stimulates endogenous surfactant synthesis in premature infants with RDS, with synthesis rates increasing by 1.3 mg/kg/day per dose of surfactant administered. 8

Emerging Approaches

Continuous positive airway pressure (CPAP) with or without surfactant may reduce the need for additional surfactant and incidence of bronchopulmonary dysplasia. 1, 5

• The INSURE approach (intubation, surfactant administration, and extubation to CPAP) shows efficacy in reducing the need for mechanical ventilation. 1
• Fully non-invasive surfactant nebulization represents the next frontier in neonatology, with studies demonstrating safety and potential in surfactant-deficient animals and preterm infants. 9