Less Invasive Surfactant Administration in Extreme Preterm Infants: A Systematic Review and Meta-Analysis

Surfactant therapy is performed in different ways in respiratory distress syndrome. Surfactant therapy in spontaneously breathing infants <28 weeks' gestation (LIST/MIST) was compared to intubation with different periods of mechanical ventilation (MV/intubation; INSURE) for efficacy and safety.

This systematic review and meta-analysis followed PRISMA guidelines with PROSPERO registration (CRD42025630748) using GRADE recommendations. Primary outcomes were BPD at 36 weeks' postmenstrual age, MV in first 72 h; and death before discharge. Secondary outcomes were intraventricular hemorrhage (IVH), necrotizing enterocolitis, retinopathy of prematurity (ROP), periventricular leukomalacia, and pneumothorax.

No RCT compared directly LISA/MIST versus INSURE in infants <28 weeks. A total of twenty-six studies were included and 12 studies in quantitative analysis were included. LISA/MIST compared to INSURE was not different in reducing BPD; or death; but reduced MV within 72 h (relative risk [RR], 0.70; 95% confidence interval [CI], 0.55-0.90; events/n = 58/153; INSURE events/n = 82/144). This effect was not detectable when only RCTs were analyzed. Compared to intubation, LISA/MIST reduced BPD (RR, 0.76; 95% CI, 0.59-0.97, n = 6,585), MV (RR, 0.61; 95% CI, 0.45-0.82, n = 6,197), death (RR, 0.63;95% CI, 0.54-0.74, n = 6,597), 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 not possible due to small numbers.

LISA/MIST reduced MV, but not 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.