Efficacy of Less Invasive Surfactant Administration (LISA) in Preterm Neonates With Respiratory Distress Syndrome: A Systematic Review and Meta-Analysis

Abstract

Background:

Less invasive surfactant administration (LISA) is increasingly used to treat respiratory distress syndrome (RDS) in preterm infants, but variation in treatment effects across clinical subgroups remains unclear.

Methods:

We conducted a systematic review and meta-analysis of randomized controlled trials published between 2010 and 2024 in MEDLINE, EMBASE, and CENTRAL comparing LISA with INtubation-SURfactant-Extubation (INSURE) in preterm infants with RDS. Random-effects generalized linear mixed models estimated pooled odds ratios with 95% confidence intervals. Prespecified subgroup analyses evaluated gestational age, surfactant type, antenatal corticosteroid exposure, and sedation.

Results:

Twenty-one trials including 2656 infants were analyzed. LISA was associated with lower odds of bronchopulmonary dysplasia, death, BPD or death, intubation or mechanical ventilation, and severe intraventricular hemorrhage. Greater benefits were observed in infants ≤ 34 weeks and those with higher antenatal steroid exposure.

Conclusion:

LISA improves key outcomes compared with INSURE and may provide greater benefits in specific clinical subgroups.

Keywords

respiratory distress syndrome surfactant therapy less invasive surfactant administration preterm infants meta-analysis neonatal intensive care

Introduction

Respiratory distress syndrome (RDS) is a leading cause of morbidity and mortality among preterm infants, primarily due to insufficient pulmonary surfactant production resulting from immature lung development. Standard management of RDS includes antenatal corticosteroids, respiratory support, and surfactant replacement therapy, alongside supportive care aimed at reducing disease severity and improving outcomes.¹ Surfactant therapy can be administered via several techniques. Historically, surfactant was delivered as a bolus through an endotracheal tube (ETT) with ongoing mechanical ventilation. For infants on non-invasive support, the INtubation-SURfactant-Extubation (INSURE) method, short intubation for surfactant delivery followed by rapid extubation to CPAP, has demonstrated protective effects against ventilator-induced lung injury.² However, INSURE often requires sedative premedication and may delay extubation due to respiratory suppression.

The less invasive surfactant administration (LISA) technique, recommended by recent European guidelines, involves delivering surfactant via a thin catheter while maintaining spontaneous breathing on CPAP.³ This method allows gradual instillation of surfactant in small aliquots, reducing the need for mechanical ventilation and associated complications.⁴ LISA has been widely adopted across Europe, with large cohort studies reporting improved clinical outcomes.⁵

Previous meta-analyses have suggested that LISA may reduce the risk of bronchopulmonary dysplasia (BPD), mortality, and early intubation compared with traditional ETT-based surfactant delivery.⁴ Network meta-analyses have further indicated that LISA may be the most effective strategy for minimizing the composite outcome of death or BPD at 36 weeks’ postmenstrual age.⁶ The effectiveness has been further confirmed by several systematic literature reviews and meta-analyses.^7
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However, these findings are limited by methodological constraints, including small sample sizes, heterogeneity in study designs, and evolving clinical practices. Moreover, the generalizability of these findings remains uncertain, particularly given the variability in gestational age, healthcare settings, and implementation protocols. Understanding how such clinical variation may influence the efficacy of LISA is critical for informing its optimal use across diverse patient populations. This systematic literature review (SLR) and meta-analysis is designed to identify and synthesize data from randomized controlled trials (RCTs) that assess the effectiveness of LISA in preterm infants with established or potential risk for developing RDS. To enhance clinical relevance, we applied comprehensive subgroup analyses across both procedural and clinical categories. This approach enables the identification of differential treatment effects, offering insights into how patient- specific factors may influence outcomes. By aligning with principles of precision medicine, the study supports more individualized strategies for surfactant administration in neonatal care. The review protocol was registered in PROSPERO (CRD42024599816).

Methods

Eligibility Criteria and Study Design

This review considered RCTs comparing LISA with surfactant administration via the INSURE technique in preterm infants with or at risk of RDS. Studies comparing LISA to surfactant administration via ETT with delayed extubation were excluded from efficacy analyses due to clinical differences in intervention timing and respiratory support strategy. Eligible studies enrolled preterm infants (<37 weeks gestational age) with established RDS or at risk of developing RDS, as defined by the original study authors. Studies were excluded if they enrolled non-preterm infants, did not meet RDS-related criteria, or included infants with severe congenital anomalies or congenital diseases affecting respiratory function. The intervention of interest was LISA, defined as surfactant delivery via a thin catheter while the infant remains on non-invasive respiratory support (eg, CPAP). Studies using alternative terminology (eg, MIST, SurE, MISA, NISA, TCA) were eligible in the SLR if the intervention met the core definition. Comparisons in meta-analysis were restricted to LISA versus INSURE. Efficacy outcomes of interest included air leak/pneumothorax, BPD, death during first hospitalization, combined outcome of death or BPD, need for additional surfactant administration, need for intubation or mechanical ventilation within 72 hours, and severe intraventricular hemorrhage (IVH).

Literature Search and Study Selection

A comprehensive search was conducted using MEDLINE, EMBASE, and CENTRAL via the Ovid platform. Keywords and MeSH terms related to preterm infants and surfactant administration techniques were used. The search strategy was designed as an update to a previously published Cochrane systematic review that identified RCTs comparing LISA and INSURE through 2019.⁴ Therefore, our electronic database search covered studies published in English from 2020 to September 10, 2024. RCTs published between 2010 and 2019 were identified from the prior Cochrane review and were reassessed for eligibility according to the inclusion criteria of the present analysis. Full search strategies are provided in Supplemental Material 1. Study selection followed a 2-phase process using DistillerSR^®, a web-based systematic review management platform that supports AI-assisted screening and reviewer collaboration. In Phase 1, after duplicate removal, titles and abstracts were screened by a single reviewer using predefined eligibility criteria. Records excluded during this phase but flagged by the AI model with an inclusion probability > 85% were re-evaluated by a second reviewer. In Phase 2, full-text articles were independently assessed by 2 reviewers, with disagreements resolved by a third. The process was summarized using a PRISMA flow diagram.

Data Extraction and Risk of Bias

Data were extracted using a standardized Excel^® template by 2 independent reviewers, with discrepancies resolved by a third. Non-numeric data were extracted by 1 reviewer and verified by another. For studies with multiple publications, the most comprehensive report was used as the primary source. Risk of bias for RCTs was assessed using the Revised Cochrane Risk of Bias Tool (RoB 2)¹¹ by 1 reviewer and validated by a second. Details of the tool are provided in Supplemental Material 2.

Meta-Analysis Feasibility Assessment

All studies identified from the systematic literature review were considered for meta-analysis feasibility assessment, focusing on the comparability in study design, patient characteristics, treatment characteristics, and outcome reporting across studies. Clinical experts were consulted regarding the interpretation of study and outcome comparability to inform the feasibility of meta-analysis.

Statistical Analysis and Reporting Bias

Treatment effects for dichotomous outcomes were estimated using odds ratios (ORs) with 95% confidence intervals (CIs). Meta-analyses were conducted using generalized linear mixed models (GLMM) for pairwise comparisons between LISA and INSURE. Analyses were performed in R (v4.4.3) using the metabin function. The GLMM was specified using the UM. FS model option, with between-study variance (τ²) estimated by maximum likelihood within the model. Random-effects models were selected as the primary approach due to expected heterogeneity. Funnel plots and Harbord’s test were generated for all outcomes to assess reporting bias and small-study effects. Outcomes based on fewer than 10 studies were considered exploratory.¹² Statistical heterogeneity was assessed using the Q statistic, I², τ², and prediction intervals. I² thresholds were: 0% to 24% (none), 25% to 49% (low), 50% to 74% (moderate), and 75% to 100% (high).

Subgroup Analyses

Subgroup analyses were conducted for outcomes with ≥3 contributing studies to explore potential variation in treatment effects across clinically and procedurally relevant strata. Six predefined scenarios included: Gestational age ≤ 34 weeks, use of purpose-designed LISA catheters, use of Curosurf^® surfactant, no mandatory pre-procedural medications, no sedation and ≥50% antenatal steroid exposure. These Subgroup analyses were considered exploratory and were not based on prespecified formal interaction testing.

Ethical Approval and Informed Consent

This study is a systematic review and meta-analysis based exclusively on previously published data. No individual participant data were collected, and no human subjects were directly involved. Therefore, ethical approval and informed consent were not required.

Results

Study Selection and Characteristics

The systematic literature review conducted in September 10, 2024 yielded 790 unique records. During title and abstract screening, performed with AI-assisted prioritization, 39 records were retained for full-text assessment and 751 were excluded. Eight records that had been initially excluded were flagged for reassessment and were reviewed by a second reviewer; however, none met the eligibility criteria for inclusion. Following screening, 28 studies were eligible for full review, including 13 newly identified studies and 15 previously included in an earlier meta-analysis (Figure 1). Among these, 21 RCTs (2656 preterm infants) met the criteria for inclusion in the efficacy analysis comparing LISA with the INSURE. Seven RCTs were eligible for the SLR but excluded from the efficacy analysis due to comparators out of scope, with comparators being ETT with delayed extubation, CPAP continuation, or different types of catheters for LISA. As shown in Table 1, the included trials were conducted across a diverse range of countries, including India (28.5%), China (14.3%), Iran (28.6%), Turkey (9.5%), Pakistan (9.5%), Egypt (4.8%), and Romania (4.8%), with enrollment periods spanning from 2010 to 2024. Sample sizes ranged from 31 to 488 participants. Fourteen studies enrolled infants with gestational age below 34 weeks, with several of these setting even lower thresholds, including gestational age below 32 weeks. Six studies extended inclusion up to 36 weeks, and 1 study included infants up to 37 weeks. Surfactant administration was reported to occur within the first 6 to 12 hours of life in 9 studies. FiO₂ thresholds were reported in 20 studies, with >40% in 9 studies and >30% in 11 studies at enrollment, randomization, or surfactant administration. Non-invasive respiratory support using CPAP or NCPAP was documented in 18 studies, 2 studies used NIPPV, and 1 study used either NCPAP or NIPPV. Intubation in the delivery room was explicitly excluded in 17 studies. Additional details about study selection and characteristics are provided in Supplemental Material 3. Supplemental Table S1 presents baseline patient characteristics, showing mean gestational ages ranging from 27.6 to 34.1 weeks and mean birth weights ranging from 1,034 to 2,219 g. Antenatal steroid exposure varied substantially, with complete course rates from 3% to 93%. Supplemental Table S2 summarizes the sample size in each treatment group (LISA and INSURE) and the rates of the efficacy outcomes, with LISA consistently associated with lower rates of BPD, early intubation, and mortality compared to INSURE. Supplemental Table S3 presents the risk of bias assessments for each study using the RoB 2 tool. 3 studies were rated low risk, 13 had some concerns, and 5 were high risk, primarily due to missing data or randomization issues.

Figure 1.

PRISMA flow diagram for studies searches.

Table 1.

Characteristics and Main Eligibility Criteria of Studies Included in Meta–Analysis.

Author yearStudy name, Trial ID^†	Country	Enrollment years	Treatment groups and sample size	Gestational age	RDS status	Age at enrollment	FiO₂ requirement	CPAP	Intubation in the delivery room
Akcay et al., 2021¹³	Turkey	NR	• LISA: 42 • INSURE: 36 • Total: 78	<34 weeks	Infants with signs of RDS	Within 2 hours of life	40% if GA > 26 weeks> 30 % if GA < 26 weeks	NCPAP	NR
Anand et al., 2022¹⁴ (CTRI/ 2020/05/025360)	India	2020 (first case)	• LISA: 74 • INSURE: 76 • Total: 150	26-34 weeks	Infants with signs of RDS	Within 6 hours of life	>30%	NCPAP	Not allowed
Bao et al., 2015¹⁵ (ChiCTR–ICR–15006001)	China	2012	• LISA: 47 • INSURE: 43 • Total: 90	28-32 weeks	Infants with RDS and in need of surfactant administration within 2 hours after birth	Within 2 hours of life	≥30% if GA 28 to 29 weeks# ≥35% if GA 30 to 32 weeks#	CPAP	Not allowed
Boskabadi et al., 2019¹⁶	Iran	2013-2015	• LISA: 20 • INSURE: 20 • Total: 40	<32 weeks	Infants with RDS	NR	≥40%	NCPAP	NR
Choupani et al., 2018¹⁷	Iran	2016-2017	• LISA: 52 • INSURE: 52 • Total: 104	28-37 weeks	Infants with signs of RDS	Within 1 hour of life	>40%#	NCPAP	Not allowed
Cucerea et al., 2023¹⁸	Romania	2018-2021	• LISA: 68 • INSURE: 34 • Total: 102	<32 weeks	Infants with RDS	Within 2 hours of life	>30%	NCPAP	Not allowed
Gupta et al., 2020¹⁹ (CTRI/ 2019/03/017992)	India	2019	• LISA: 29 • INSURE: 29 • Total: 58	28-34 weeks	Infants with RDS	Within 6 hours of life	>30%#	NIPPV	Not allowed
Halim et al., 2019²⁰	Pakistan	2017	• LISA: 50 • INSURE: 50 • Total: 100	<34 weeks	Infants with RDS	Within 12 hours of life	>40%	NCPAP	Not allowed
Han et al., 2020²¹ (MISA study, NCT04077333)	China	2017-2018	• LISA: 176 • INSURE: 168 • Total: 344	<31 weeks +6 days	Infants with RDS or signs of RDS and in need of surfactant administration within 6 hours after birth	Within 6 hours of life	>40%	NCPAP	Not allowed
Jena et al., 2019²²	India	2013-2017	• LISA: 175 • INSURE: 175 • Total: 350	≤34 weeks	Infants with RDS	Within 6 hours of life	>40%	CPAP	Not allowed
Kaleem et al., 2023²³	Pakistan	2021-2022	• LISA: 36 • INSURE: 36 • Total: 72	<34 weeks	Infants with RDS	NR*	>30%	CPAP	NR
Kanmaz et al., 2013²⁴ (NCT01329432)	Turkey	2010-2011	• LISA: 100 • INSURE: 100 • Total: 200	<32 weeks	Infants with RDS	Within 2 hours of life	≥40%#	NCPAP	Not allowed
Khandwal et al., 2024²⁵	India	2022-2022	• LISA: 70 • INSURE: 70 • Total: 140	28-34 weeks	Infants with signs of RDS	Within 6 hours of life	NR	CPAP	Not allowed
Mirnia et al., 2013²⁶	Iran	2010-2012	• LISA: 66 • INSURE: 70 • Total: 136	27-32 weeks	Infants with RDS	NR	>30%#	CPAP	NR
Mishra et al., 2023²⁷ (CTRI/ 2022/01/039147)	India	NR	• LISA: 75 • INSURE: 75 • Total: 150	28-36 weeks	Infants with RDS	NR§	>30%#	NIPPV	Not allowed
Mohammadizadeh et al., 2015²⁸	Iran	2012-2013	• LISA: 19 • INSURE: 19 • Total: 38	28-34 weeks	Infants with RDS	Within 1 hour of life	>30%*	NCPAP	Not allowed
Mosayebi et al., 2017²⁹ (IRCT2014080716937N4)	Iran	2013-2014	• LISA: 27 • INSURE: 26 • Total: 53	28-36 weeks +6 days	Infants with RDs	Within 12 hours of life	>40%#	NCPAP	Not allowed
Pareek et al., 2021³⁰ (CTRI/ 2019/04/018701)	India	2019-2020	• LISA: 20 • INSURE: 20 • Total: 40	28-36 weeks +6 days	Infants with RDs	Within 24 hours of life	>30 % if GA < 30 weeks # >40% if GA ≥ 30 weeks#	NCPAP or NIPPV	Not allowed
Sabzehei et al., 2022³¹ (IRCT20160523028008N81)	Iran	2019-2020	• LISA: 56 • INSURE: 56 • Total: 112	28-36 weeks	Infants with RDS	NR	>40%#	NCPAP	Not allowed
Sayed et al., 2024³²	Egypt	NR	• LISA: 45 • INSURE: 45 • Total: 90	28-36 weeks	Infants with RDS	Within 6 hours of life	>30%	CPAP	Not allowed
Yang et al., 2020³³	China	2017-2018	• LISA: 47 • INSURE: 50 • Total: 97	33-36 weeks + 6 days	Infants with RDS	Within 12 hours of life	>40%	NCPAP	Not allowed

Note. ^†Study name and register ID if reported. #FiO₂ requirement at the time of randomization or surfactant administration. *Mean age was 1.27 ± 0.40 days in the LISA group and 1.23 ± 0.48 days in the INSURE group. §Mean age was 2.98 ± 0.70 hours in the LISA group and 2.80 ± 0.79 hours in the INSURE group.

Abbreviations: AMV, The Avoiding Mechanical Ventilation; CPAP, Continuous Positive Airway Pressure; ETT, Endotracheal; Tube; INSURE, INtubation-SURfactant-Extubation; LISA, Less Invasive Surfactant Administration; MAC, Multi Access catheter^®; MIST, Minimally Invasive Surfactant Therapy; NICU, Neonatal Intensive Care Unit; NR, Not reported; RDS, Respiratory distress syndrome; SNIPPV, Synchronized Nasal Intermittent Positive Pressure Ventilation; UK, United Kingdom; US, United States

Overall Population

Seven efficacy outcomes were analyzed. Figure 2 shows forest plots for each outcome, comparing LISA with INSURE in randomized controlled trials. LISA was associated with a statistically significant reduction in the risk of 5 key outcomes: BPD at 36 weeks postmenstrual age (PMA; OR: 0.57 [0.36, 0.88]), death during first hospitalization (OR: 0.64 [0.46, 0.87]), composite outcome of BPD or death (OR: 0.44 [0.26, 0.74]), need for intubation or mechanical ventilation within 72 hours (OR: 0.54 [0.41, 0.71]), and severe IVH (Grade 3 or 4; OR: 0.59 [0.36, 0.99]). No significant differences were observed for air leak/pneumothorax (OR: 0.62 [0.38, 1.02]) or need for additional surfactant administration (OR: 0.94 [0.74, 1.19]).

Figure 2.

Forest plots for pairwise comparison of efficacy outcomes between LISA and INSURE in randomized controlled trials: (A) Air leak/pneumothorax, (B) BPD, (C) Death during first hospitalization, (D) Death/ BPD, (E) Need for additional surfactant administration, (F) need for intubation/mechanical ventilation within 72 hours and (G) Severe IVH. *Forest plots display ORs with 95% CIs for each outcome. The vertical dashed line represents the line of no effect (OR = 1). Estimates to the left of the line favor LISA over INSURE. All analyses were conducted using both common and random-effects models.

Heterogeneity across studies was generally low (I² < 25%) for most outcomes, supporting the consistency of findings. Funnel plot assessments showed no significant publication bias for most outcomes (Supplemental Material 3, Supplemental Figures S1-S7 ). However, for the composite outcome of BPD or death, exploratory analysis indicated possible non-reporting bias (Harbord test P = .027).

Subgroup Analyses

Subgroup analyses were conducted to explore potential variation in treatment effects across clinically and procedurally relevant strata (Table 2). Six predefined scenarios were evaluated: gestational age ≤ 34 weeks, use of Curosurf^® as the surfactant product, absence of mandatory pre-procedural medications, absence of sedation, and antenatal steroid exposure in ≥50% of infants. The scenario involving catheters specifically designed for LISA was excluded due to insufficient data, with only 1 study reporting relevant outcomes.

Table 2.

Overall Population and Subgroup Analyses Results for Efficacy Outcomes in RCTs, with Pairwise Comparison using Random-Effects.

Outcome	No. of studies for base-case*	Overall Population	Gestational age ≤34 weeks	Curosurf^® as the surfactant product	No mandatory pre-procedural medications	No sedation	Antenatal steroids in ≥50% of infants
Number of studies for analysis	-	9-18	5-14	6-12	4-13	4-11	4-8
Air leak/pneumothorax	12 (13)	0.62 [0.38, 1.02]	0.66 [0.36, 1.18]	0.67 [0.38, 1.19]	0.68 [0.38, 1.2]	0.61 [0.29, 1.29]	0.56 [0.3, 1.03]
BPD at 36 weeks PMA	11	0.57 [0.36, 0.88]	0.45 [0.26, 0.76]	0.56 [0.33, 0.96]	0.68 [0.27, 1.73]	0.47 [0.23, 0.99]	0.38 [0.21, 0.71]
Death during first hospitalization	16 (18)	0.64 [0.46, 0.87]	0.66 [0.48, 0.91]	0.72 [0.4, 1.28]	0.7 [0.51, 0.97]	0.92 [0.61, 1.39]	0.6 [0.36, 1]
Death/BPD	9	0.44 [0.26, 0.74]	0.32 [0.21, 0.48]	0.43 [0.26, 0.7]	0.74 [0.2, 2.75]	0.6 [0.2, 1.83]	0.32 [0.21, 0.48]
Need for additional surfactant administration	18	0.94 [0.74, 1.19]	0.91 [0.69, 1.2]	0.81 [0.59, 1.11]	1.02 [0.77, 1.35]	0.87 [0.61, 1.25]	0.78 [0.56, 1.09]
Need for intubation/mechanical ventilation within 72 hours	17	0.54 [0.41, 0.71]	0.47 [0.36, 0.61]	0.61 [0.46, 0.81]	0.49 [0.33, 0.72]	0.55 [0.4, 0.77]	0.55 [0.39, 0.76]
Severe IVH (Grade 3 or 4)	8 (9)	0.59 [0.36, 0.99]	0.7 [0.4, 1.22]	0.57 [0.28, 1.17]	0.62 [0.37, 1.05]	0.66 [0.38, 1.17]	0.55 [0.26, 1.16]

Note. Data is reported as odds ratio [95% confidence interval] for LISA versus INSURE/ETT, where an odds ratio < 1 favors LISA. A 95% CI that does not include 1 indicates a statistically significant difference between LISA and INSURE/ETT, as indicated by blue font.

Studies with 0 events in both arms were not included in the analysis, and the total no. of studies including such studies are presented in parenthesis

Abbreviations: BPD, Bronchopulmonary Dysplasia; INSURE, INtubation-SURfactant-Extubation; IVH, Intraventricular Hemorrhage; LISA, Less Invasive Surfactant Administration; NA, Not applicable; PMA, Postmenstrual Age; RCT, Randomized Controlled Trial.

Across all evaluated scenarios, the direction of treatment effects was generally consistent with the overall population findings, but the magnitude and statistical significance varied, reflecting potential variation across subgroups. The reduction in the need for intubation or mechanical ventilation within 72 hours was replicated across all subgroup analyses, with odds ratios ranging from 0.47 to 0.61 and confidence intervals consistently excluding unity. However, for BPD and the composite outcome of death/BPD, the effect was notably stronger among infants ≤ 34 weeks gestation (OR: 0.45 [0.26, 0.76] and OR: 0.32 [0.21, 0.48], respectively) and those with antenatal steroid exposure ≥ 50% (OR: 0.38 [0.21, 0.71] and OR: 0.32 [0.21, 0.48], respectively), with statistically significant reductions in both outcomes. For other outcomes results were directionally consistent with the base-case but did not consistently reach statistical significance across all scenarios. Severe IVH showed a significant reduction in the base-case analysis, but none of the subgroup scenarios replicated this finding.

Detailed results available in the Supplemental Material 3 Supplemental Tables S4-S10, including the number of patients and events in each treatment group, odds ratios with confidence intervals, p-values, prediction intervals, degrees of freedom, I², τ², and p-values for heterogeneity.

Discussion

This systematic review and meta-analysis of 21 RCTs involving 2656 preterm infants offers consistent evidence that LISA is more effective than the INSURE technique in improving outcomes for neonates with or at risk of RDS. LISA was associated with statistically significant lower risk of BPD at 36 weeks PMA, death during first hospitalization, the composite outcome of BPD or death, early intubation or mechanical ventilation, and severe IVH. These outcomes are critical indicators of neonatal morbidity and mortality and have long-term implications for neurodevelopmental health.^1,3
-6 The consistency of pooled estimates across studies is supported by low heterogeneity (I² < 25%) for most efficacy outcomes. Subgroup analyses revealed meaningful variation in effect size and statistical significance, particularly for BPD and death/BPD, where the benefit of LISA was more pronounced among infants ≤ 34 weeks gestation and those with antenatal steroid exposure ≥ 50%.

The observed reductions in BPD and early intubation are particularly relevant given the growing emphasis on non-invasive respiratory support in neonatal care. These findings align with the 2022 European Consensus Guidelines, which recommend LISA as the preferred method of surfactant administration in spontaneously breathing preterm infants.³ Although most studies included in our meta-analysis were conducted outside of Europe and the United States, our results align with the direction of evidence that informed these guidelines. In the United States, LISA has not yet been widely adopted, but interest is increasing as clinicians consider its integration into non-invasive respiratory strategies.³⁴ However, high-quality RCTs from U.S. settings remain limited. This meta-analysis provides timely and actionable evidence to support broader implementation of LISA globally.

The results of our meta-analysis align with prior evidence supporting the efficacy of LISA over INSURE but also extend the literature in scope and analytical depth. The 2021 Cochrane review⁴ which synthesized 12 RCTs, several from high-income countries such as Germany and Canada, reported significant reductions in BPD, mortality, early intubation, and severe IVH with LISA. Despite variation in study populations and timeframe, the magnitude and direction of effect sizes reported in that review align closely with our findings. However, subgroup analyses were limited, limiting insight into treatment heterogeneity. Similarly, the network meta-analysis by Isayama et al,⁶ which include studies from Europe and North America, suggested that LISA is likely the most favorable strategy for reducing the composite outcome of death or BPD. Their pooled effect estimates were generally consistent with ours, although stratification by clinical characteristics was not reported. A subsequent systematic review by Silveira et al,⁹ evaluating 16 RCTs published between 2012 and 2020 from both high- and middle-income regions. Their findings reaffirmed the benefits of LISA, showing reduced risk of BPD, mortality, and mechanical ventilation. Yet, subgroup analyses were limited, and stratification by gestational age or antenatal steroid exposure was not feasible. Our analysis builds on this evidence base by incorporating more recent randomized trials published between 2020 and 2024 and by applying prespecified subgroup analyses to interrogate potential differential treatment effects

Importantly, our subgroup analyses revealed meaningful variation in treatment effects across clinical and procedural strata. While the direction of benefit with LISA was preserved across all subgroups, the magnitude of effect differed substantially. For example, the reduction in BPD and the composite outcome of death or BPD was notably stronger among infants ≤ 34 weeks gestation and those with antenatal steroid exposure ≥ 50%, suggesting that these populations may derive greater benefit from LISA. In contrast, the association with severe IVH was less stable, as subgroup analyses did not replicate the base-case result, potentially reflecting heterogeneity in IVH risk factors or limitations in outcome ascertainment. Procedural factors also warrant consideration. Although LISA is defined by surfactant administration via a thin catheter during spontaneous breathing on CPAP, only 2 RCTs used catheters specifically designed for this technique, and only 1 reported efficacy outcomes. Curosurf was the most used surfactant across studies, but the extent to which these findings apply to other formulations is uncertain.

The number of studies and patients contributing to each subgroup scenario varied and should be considered when interpreting consistency and precision (Supplemental Material 3, Supplemental Figures S8-S9 ). In overall population, patient counts ranged from 1010 to 2264 across 8 to 18 studies per outcome. Subgroup analyses were supported by smaller evidence bases. For example, the gestational age ≤ 34 weeks scenario included up to 1671 patients, while the antenatal steroid exposure ≥ 50% subgroup was informed by 4 to 8 studies, with patient counts ranging from 433 to 1131. The Curosurf^® subgroup included 6 to 12 studies and up to 1140 patients, depending on the outcome. These differences in sample size and study representation may influence the stability of estimates and highlight the need for cautious interpretation, particularly in procedural subgroups.

Several limitations should be considered. First, while the included RCTs were methodologically sound, variability in patient characteristics (eg, gestational age, birth weight, antenatal steroid exposure), procedural implementation, and co-interventions may affect the generalizability of findings. While a random-effects model was used to account for between-study heterogeneity, statistical measures such as I² may be less stable when the number of included studies is limited, and residual clinical heterogeneity cannot be fully excluded. Second, the exclusion of non-randomized studies from the efficacy synthesis limits insights into real-world effectiveness. Furthermore, the possibility of selective outcome reporting or publication bias cannot be entirely excluded, particularly given the limited number of available trials for certain outcomes. Future studies should explore pragmatic trial designs or high-quality observational data to complement RCT findings. Third, none of the included RCTs reported long-term clinical outcomes, such as neurodevelopmental status, long-term respiratory morbidity, or rehospitalization rates. Consequently, our findings are limited to short-term efficacy outcomes, and the long-term safety and developmental implications of LISA remain uncertain. Fourth, data limitations precluded subgroup analyses for certain clinically relevant factors, such as catheter type, surfactant formulation, and timing of administration. These procedural variables may influence outcomes and warrant further investigation. Lastly, several subgroup analyses were based on a limited number of contributing studies. Meta-analyses with a small number of studies may yield less precise pooled estimates, and between-study variance may be estimated with greater uncertainty. Consequently, the ability to detect consistent differences across subgroups may be limited. These analyses were intended to synthesize the available evidence and identify potential patterns to inform future research, rather than to draw definitive conclusions.

Conclusion

This meta-analysis confirms that LISA is associated with improved clinical outcomes compared to the INSURE technique in preterm infants with RDS. Beyond confirming overall efficacy, our findings highlight clinically meaningful variation in treatment effects across subgroups, particularly among infants ≤ 34 weeks gestation and those with antenatal steroid exposure ≥ 50%. These differences underscore the importance of tailoring surfactant strategies to patient-specific factors. Further research is warranted to evaluate long-term neurodevelopmental outcomes, optimize procedural protocols, and assess comparative effectiveness and cost-efficiency across diverse clinical settings.

Supplemental Material

sj-docx-1-gph-10.1177_30502225261453435 – Supplemental material for Efficacy of Less Invasive Surfactant Administration (LISA) in Preterm Neonates With Respiratory Distress Syndrome: A Systematic Review and Meta-Analysis

Supplemental material, sj-docx-1-gph-10.1177_30502225261453435 for Efficacy of Less Invasive Surfactant Administration (LISA) in Preterm Neonates With Respiratory Distress Syndrome: A Systematic Review and Meta-Analysis by Xuezheng Sun, Shaked Yarza, Yuting Kuang, Shruti Sharma, Jenny Uyei, Subhan Khalid and Daniel Fuentes in Sage Open Pediatrics

Supplemental Material

sj-docx-2-gph-10.1177_30502225261453435 – Supplemental material for Efficacy of Less Invasive Surfactant Administration (LISA) in Preterm Neonates With Respiratory Distress Syndrome: A Systematic Review and Meta-Analysis

Supplemental material, sj-docx-2-gph-10.1177_30502225261453435 for Efficacy of Less Invasive Surfactant Administration (LISA) in Preterm Neonates With Respiratory Distress Syndrome: A Systematic Review and Meta-Analysis by Xuezheng Sun, Shaked Yarza, Yuting Kuang, Shruti Sharma, Jenny Uyei, Subhan Khalid and Daniel Fuentes in Sage Open Pediatrics

Footnotes

Acknowledgements

The authors gratefully thank Dr. Elizabeth E. Foglia from the Devision of Neonatology, Children’s Hospital of Philadelphia, for her valuable contributions throughout the study, including input on protocol development and interpretation of the results.

ORCID iD

Shaked Yarza

Ethical Considerations

This study is a systematic literatuture review based on previously published studies and does not involve human participants, human data, or animal subjects. Therefore, ethinical approval was not required.

Consent to Participate

Not applicable.

Author Contributions

XS and DF contributed to the conception of the study. XS, DF, JU, SK, and YK contributed to the design of the study and protocol development. SS and YK contributed to the literature search and data extraction. YK and SK performed data analysis. XS, DF, SY, YK, and JU contributed to results interpretation. SY and XS drafted the manuscript. All authors reviewed and approved the final manuscript.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was sponsored and funded by Chiesi USA.

Declaration of Conflicting Interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: XS, SY, and DF are employees of Client company, which funded this research. YK, SS, JU and SK are employees of IQVIA, Inc. which provides consultancy services to pharmaceutical and biotech companies.

Supplemental Material

Supplemental material for this article is available online.

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