Supplementary Material for: Less invasive surfactant administration (LISA) in extreme preterm infants – A systematic review and meta-analysis

Background Surfactant therapy is performed in different manners in respiratory distress syndrome. Surfactant therapy in spontaneously breathing infants <28weeks’ gestation (LIST/MIST) was compared to intubation with different periods of mechanical ventilation (MV/intubation; INSURE) for efficacy and safety.Methods This systematic review and meta-analysis followed PRISMA guidelines with PROSPERO registration (CRD42025630748) using GRADE recommendations. Primary outcomes were BPD at 36weeks’ postmenstrual age, MV in first 72hours; and death before discharge. Secondary outcomes were IVH, NEC, ROP, PVL, and pneumothorax.ResultsNo RCT compared directly LISA/MIST versus INSURE in infants <28weeks. Twenty-six studies in the qualitative synthesis and 12 studies in quantitative analysis were included. LISA/MIST compared to INSURE was not different in BPD; or death; but reduced MV within 72hours (RR,0.70;95%CI,0.55–0.90; events/n=58/153; INSURE events/n=82/144). This effect was not detectable when only RCTs were analysed. Compared to intubation, LISA/MIST reduced BPD (RR,0.76; 95% CI,0.59–0.97, n=6585), MV (RR,0.61; 95% CI,0.45–0.82,n=6197), death (RR,0.63;95% CI,0.54–0.74, n=6597), IVH (RR,0.62;95% CI,0.54–0.73), pneumothorax (RR,0.58; 95% CI,0.46–0.73), and ROP (RR,0.61;95% CI,0.50–0.73). Composite outcome analysis BPD/ death was impossible due to small numbers. Discussion/ConclusionLISA/MIST reduced MV, but not either BPD, or separately- death when compared with INSURE. The findings should be interpreted cautiously due to limited power and competing risk dynamics in extremely preterm infants.