Safety of Less Invasive Surfactant Administration in Preterm Infants: A Meta-Analysis

Background: Less invasive surfactant administration (LISA) is increasingly used in preterm infants with respiratory distress syndrome (RDS). Understanding its safety profile compared to the INtubation-SURfactant-Extubation (INSURE) or endotracheal tube (ETT) techniques is essential. Objective: To evaluate the safety profile of LISA compared to INSURE/ETT in preterm infants with RDS using evidence from randomized and non-randomized studies. Methods: A systematic literature review identified studies in MEDLINE, EMBASE, and CENTRAL (2010–2024). Arm-level pooled incidence estimates were generated across RCTs and non-randomized studies, and pairwise comparisons of LISA versus INSURE/ETT were conducted in randomized controlled trials (RCTs). Analyses utilized Generalized Linear Mixed Models with random-effects. Subgroups included gestational age (≤ 34 weeks), surfactant type, antenatal steroid exposure (≥ 50%) and sedation and premedication use. Results: Nineteen RCTs (2460 infants) and 26 non-randomized studies (2360 infants) met inclusion criteria. Pairwise comparisons revealed no statistically significant differences between LISA and INSURE/ETT for apnea, bradycardia, cough, hypoxemia, or need for ≥ 2 attempts for successful catheter/ETT placement attempts; however, surfactant regurgitation/reflux occurred more frequently with LISA (OR = 2.29, 95% CI = 1.21–4.33). Adverse event rates were generally higher in non‑randomized studies, with hypoxemia the most frequently reported event across study types (≥ 24%). Subgroup findings were consistent with overall results. Conclusion: To our knowledge, this is the first meta-analysis evaluating LISA safety outcomes across both RCTs and non-randomized studies. LISA demonstrates a safety profile broadly comparable to INSURE/ETT for most outcomes. Differences observed in observational studies likely reflect variability in reporting and clinical practice. Standardized training and procedure optimization may further enhance safety.