Key messages
• Current care for preterm infants (babies born early) who are at risk of respiratory distress syndrome (lung problems causing breathing difficulties) usually involves an intervention called continuous positive airway pressure (CPAP). In these infants, giving surfactant (a coating for the lungs to make breathing easier) as a preventive measure may make little or no difference to the risk of chronic lung disease (needing long-term oxygen support), and probably slightly increases the risk of death, compared with giving surfactant only to those babies who actually develop breathing problems.
• In contrast, for preterm infants not receiving CPAP, giving surfactant preventively reduces the risk of death and may slightly reduce the risk of pneumothorax (lung injury), compared to giving surfactant only if and when breathing problems develop.
• In our view, giving all preterm infants CPAP at birth and then giving surfactant only to those who have symptoms of breathing problems may be the best approach to managing the risk of respiratory distress syndrome.
What is a preterm infant?
A preterm infant is a baby who is born early, having spent less than 37 weeks in the womb.
What is surfactant?
Surfactant is a mixture of fats and proteins produced by the body that coats the inside of the alveoli (tiny air sacs in the lungs) and helps the lungs work properly. Some preterm infants are born before their lungs produce enough surfactant, which makes it difficult for their lungs to stay open and get enough oxygen. This is called respiratory distress syndrome (RDS). Surfactant replacement therapy can be used to replace the missing surfactant.
What did we want to find out?
We wanted to know whether to give surfactant to preterm babies, preventively, that is, immediately after birth before any breathing problems occur ('prophylactic surfactant'), or only if the baby has symptoms ('selective surfactant').
Studies conducted 30 years ago suggested that preterm infants who were intubated (breathing tube placed in the airway, down the throat, and into the lungs) and were treated with prophylactic surfactant (before breathing problems occurred) had fewer RDS complications such as chronic lung disease or pneumothorax.
Newer studies, however, suggest that a better treatment approach may be using breathing support (i.e. continuous positive airway pressure (CPAP)) through a mask or nose prongs placed on the baby’s face, and applying surfactant only if breathing problems develop. This avoids putting tubes into the windpipe and giving medicines that may be unnecessary.
What did we do?
We searched for studies that tested the prophylactic versus selective use of surfactant. We combined results for infant mortality (death) within the first 28 days of life (the neonatal period) and the development of more severe lung disease that may require long-term oxygen supplementation (chronic lung disease). We looked at whether results varied if preterm babies were given CPAP to support their breathing at birth or if their mothers had received medication, such as steroids, which help the baby’s lungs mature during the prenatal period.
What did we find?
We identified 10 relevant studies that involved 3151 babies.
When considering all studies together, prophylactic surfactant probably results in little to no difference in the risk of chronic lung disease (CLD) compared to selective use of surfactant (5 studies, 1874 babies) and may slightly reduce the risk of pneumothorax (8 studies, 3094 babies). It may make little to no difference to the risk of moderate-to-severe neurodevelopmental impairment (problems with brain development) (1 study, 976 babies).
Studies where infants received CPAP showed that prophylactic use of surfactant probably slightly increases the risk of mortality compared to its selective use as a treatment once RDS symptoms have developed, and it may make little to no difference to the risk of CLD. The evidence for pneumothorax is very uncertain.
In contrast, studies where infants did not receive CPAP showed that prophylactic use of surfactant reduces mortality risk compared with giving surfactant selectively after RDS develops, and it may reduce the risk of pneumothorax slightly. The evidence for CLD is very uncertain.
In our view, the review findings favor early stabilization of breathing with CPAP for all preterm infants at risk of developing RDS and then selective use of surfactant for preterm infants showing RDS symptoms.
What are the limitations of the evidence?
People running the studies and families of babies taking part may have known which treatment was being given, which may have influenced measurements.
Not all studies provided information about everything of interest. For example, some studies did not measure longer-term infant development.
The studies did not provide enough reliable information for us to understand the effects of the age of the babies (born before 28 weeks or closer to their due date), mothers receiving steroids before giving birth, or different methods of giving the surfactant.
How up to date is this evidence?
This review updates a previous 2012 Cochrane review. The evidence is current to 31 January 2025.
Read the full abstract
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.
Objectives
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).
Search strategy
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.
Selection criteria
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.
Data collection and analysis
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.
Main results
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.
Authors' conclusions
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.
