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Respiratory distress syndrome (RDS), or hyaline membrane disease, is a common condition in preterm infants (< 37 weeks' gestation) and a leading cause of neonatal morbidity and mortality. The risk is highest in extremely preterm (< 28 weeks) and very preterm (28 to < 31 weeks) infants due to immature lung and cardiovascular development. RDS results from a deficiency or dysfunction of pulmonary surfactant, which lines the alveoli to reduce surface tension, prevent atelectasis, and protect the lungs. Surfactant is primarily composed of dipalmitoylphosphatidylcholine (DPPC), other phospholipids, and four proteins that support its function, recycling, and innate lung defense. Surfactant replacement therapy improves lung compliance, reduces the need for ventilator support, and decreases the risk of pneumothorax, death, and the combined outcome of death or bronchopulmonary dysplasia. Its widespread use has substantially improved survival among preterm infants without increasing long-term neurological or developmental disability. Various surfactant preparations, including animal-derived, synthetic, and protein or peptide-containing formulations have been evaluated. Surfactant can be administered prophylactically immediately after birth or selectively once RDS develops. Both strategies are effective, with theoretical advantages and disadvantages. Prophylactic surfactant may prevent respiratory insufficiency, reduce the need for ventilator support, and distribute surfactant more evenly in fluid-filled lungs, lowering the risk of lung injury. Selective treatment targets only infants with clinical RDS, avoiding unnecessary therapy, potential risks, and costs for those who would not benefit. Administration methods include endotracheal tube, intubation with rapid extubation, thin catheter, laryngeal mask, hypopharyngeal deposition, and, more recently, aerosolized or nebulized approaches, though the effectiveness of the latter remains unproven. For this review, a prophylactic strategy refers to intubation and bolus surfactant administration immediately after birth, while selective therapy refers to administration once evidence of RDS is present. The effect of surfactant may differ in infants stabilized early on continuous positive airway pressure (CPAP) and those whose mothers received a complete course of antenatal corticosteroids. In these infants, the benefits of prophylactic surfactant appear less pronounced than in neonates who did not receive early CPAP or antenatal steroids. In this update, we explored these factors in subgroup analyses, as in the previous version of the review. Additionally, we examined how the threshold of FiO₂ (fraction of inspired oxygen) used to initiate selective treatment, as well as the method of surfactant administration, might influence the effect of the surfactant replacement strategies.

To compare the effect of prophylactic surfactant administration versus selective surfactant administration on morbidity and mortality in preterm infants at risk of respiratory distress syndrome (RDS).

We searched CENTRAL, MEDLINE, Embase, and CINAHL on 31 January 2025. To identify any studies not captured by our search of bibliographical databases, we also searched clinical trial registers, conference proceedings, and reference lists of included studies and surfactant reviews.

We included randomized controlled trials (RCTs) and quasi-RCTs comparing the effects of prophylactic surfactant administration in preterm infants at risk of RDS versus surfactant treatment of preterm infants with established RDS.

We used standard Cochrane methods. Our main outcomes were mortality, neurodevelopmental disability, and complications of preterm birth including pneumothorax and chronic lung disease. We performed meta-analysis and expressed our results using mean difference (MD), standardized mean difference (SMD), or risk ratio (RR), with 95% confidence intervals (CIs). We used GRADE to assess the certainty of the evidence.

We identified 10 relevant individually randomized controlled trials (involving 3151 preterm infants). All trials were conducted in North America and Europe. Eight were conducted in the 1990s, and two were published more recently, at a time of greater use of antenatal steroids and nasal continuous positive airway pressure (CPAP). Nine trials were at risk of performance and detection bias. When all studies are considered, prophylactic surfactant probably results in little to no difference in the risk of chronic lung disease (CLD) at 36 weeks' postmenstrual age compared to selective use of surfactant (RR 1.13, 95% CI 1.00 to 1.28; I² = 0%; RD 0.04, 95% CI 0.00 to 0.08; NNTH 25 95% CI 13 to > 1000; I² = 0%; 5 trials, 1874 infants; moderate-certainty evidence). There may be little to no difference between the prophylactic and selective approaches in moderate to severe neurodevelopmental impairment (RR 0.83, 95% CI 0.57 to 1.21; 1 trial, 976 infants; I² not applicable; low-certainty evidence). Prophylactic surfactant may result in a slight reduction in pneumothorax compared to selective surfactant administration (RR 0.76, 95% CI 0.56 to 1.04; I² = 12%; 8 trials, 3094 infants; low-certainty evidence). In studies in which infants were stabilized on CPAP, the use of prophylactic surfactant, compared with selective surfactant administration, may make little to no difference to the risk of chronic lung disease and probably slightly increases mortality, while the evidence remains uncertain regarding the effect of prophylactic surfactant on all other outcomes, including pneumothorax. In contrast, in settings without routine use of CPAP, prophylactic surfactant reduces mortality and may reduce pneumothorax slightly, with very uncertain evidence for CLD. In our view, these findings support managing neonates at risk of respiratory distress syndrome with initial stabilization using CPAP and then selective surfactant administration. We were not able to draw conclusions about our subgroup analyses conducted according to receipt of antenatal steroids, threshold used to apply selective treatment, and method of surfactant administration, which provided evidence of low to very low certainty. There were insufficient data to carry out subgroup analysis by gestational age.

Studies of prophylactic surfactant administration in infants at risk of developing RDS that were conducted prior to widespread use of maternal prenatal steroids and routine early stabilization on CPAP demonstrated a decreased risk of mortality and slight reduction in pneumothorax compared with selective surfactant use in infants with established RDS. However, larger trials that reflect current neonatal care practices do not support this finding. Instead, they show that, compared with selective surfactant administration in infants stabilized on CPAP, prophylactic surfactant likely results in little to no difference in the risk of chronic lung disease and slightly increases mortality.