Abstract
Background
Nasal continuous positive airway pressure (NCPAP) and nasal intermittent positive pressure ventilation (NIPPV) are commonly used as initial non-invasive respiratory support in preterm infants with respiratory distress syndrome (RDS). Minimally invasive surfactant therapy (MIST) is increasingly used to reduce exposure to endotracheal intubation, but data on NIPPV compared to NCPAP during MIST remain limited. This study aimed to compare NIPPV and NCPAP as initial respiratory support during MIST in preterm infants with RDS, with the primary outcome of invasive mechanical ventilation within the first 72 h of life.
Methods
This single-center, retrospective, real-world cohort study included preterm infants (<37 weeks of gestation) with RDS who received MIST within 6 h after birth between January 2021 and January 2025. Infants were grouped according to the initial mode of non-invasive respiratory support: NIPPV (n=170) or NCPAP (n=130). The primary outcome measure was invasive mechanical ventilation (IMV) within the first 72 h of life. Between-group comparisons, multivariable logistic regression adjusted for gestational age and birth weight, inverse probability of treatment weighting, and gestational-age subgroup analyses were performed. Secondary outcome measures included neonatal morbidities, respiratory-support duration, length of hospital stay, surfactant use, and blood gas changes.
Results
Infants in the NIPPV group had lower gestational age (31.37±2.09 vs. 33.51±1.73 weeks, P<0.001) and birth weight (1.60±0.45 vs. 1.99±0.47 kg, P<0.001) than those in the NCPAP group. IMV within 72 h occurred in 46/170 infants (27.1%) in the NIPPV group and 24/130 infants (18.5%) in the NCPAP group [unadjusted risk ratio, 1.47; 95% confidence interval (CI): 0.95–2.27; P=0.08]. After adjustment for gestational age and birth weight, the association was not statistically significant (adjusted odds ratio, 0.605; 95% CI: 0.32–1.14; P=0.12), and the inverse-probability-weighted analysis yielded similar results (P=0.10). No gestational-age subgroup showed a significant difference in the primary outcome. Unadjusted rates of BPD and ROP, as well as non-invasive ventilation duration and length of hospital stay, were higher in the NIPPV group, consistent with greater baseline immaturity. Moderate or severe BPD, ROP requiring surgery, NEC, IVH, hsPDA, sepsis, pneumothorax, and repeat surfactant treatment did not differ significantly between groups. Blood gas profiles improved after surfactant treatment in both groups, with no significant post-treatment between-group differences.
Conclusions
In preterm infants with RDS receiving MIST, initial NIPPV and NCPAP were associated with no statistically significant difference in IMV requirement within 72 h after accounting for major baseline imbalances. NIPPV appears to be a feasible alternative to NCPAP in this setting, but this retrospective study cannot establish non-inferiority or causality. Larger multicenter randomized studies with prespecified stratification are warranted.
Keywords: Preterm infant, respiratory distress syndrome, minimally invasive surfactant therapy (MIST), nasal intermittent positive pressure ventilation (NIPPV), nasal continuous positive airway pressure (NCPAP)
Highlight box.
Key findings
• In this retrospective cohort of 300 preterm infants with respiratory distress syndrome receiving minimally invasive surfactant therapy (MIST), initial nasal intermittent positive pressure ventilation (NIPPV) and nasal continuous positive airway pressure (NCPAP) were not associated with a statistically significant difference in invasive mechanical ventilation within 72 h after adjustment for gestational age and birth weight; inverse probability of treatment weighting and gestational-age subgroup analyses yielded consistent results.
What is known and what is new?
• NCPAP is an established initial non-invasive support strategy for preterm respiratory distress syndrome, and NIPPV may reduce respiratory failure in selected preterm populations; however, direct comparative evidence during MIST remains limited.
• This real-world study directly compared initial NIPPV and NCPAP during MIST and addressed major baseline imbalances using multivariable adjustment, inverse probability of treatment weighting, and gestational-age-stratified analyses.
What is the implication, and what should change now?
• NIPPV may be considered a feasible alternative to NCPAP during MIST when clinically indicated and accompanied by close monitoring. These observational findings do not establish equivalence, non-inferiority, or causality; multicenter randomized trials with prespecified gestational-age stratification and standardized respiratory-support protocols are warranted.
Introduction
Neonatal respiratory distress syndrome (RDS) is primarily caused by surfactant deficiency and pulmonary structural and functional immaturity. It remains a major cause of respiratory morbidity in preterm infants, as its incidence is inversely proportional to gestational age (1). Contemporary RDS management emphasizes early non-invasive respiratory support, careful use of oxygen, early selective surfactant treatment, and avoidance of unnecessary endotracheal intubation and invasive mechanical ventilation (IMV) (2).
Minimally invasive surfactant therapy (MIST), also referred to as less invasive surfactant administration in some settings, allows surfactant to be delivered through a thin catheter while the infant continues spontaneous breathing under non-invasive support. This approach has been associated with reduced use of IMV and has been increasingly incorporated into neonatal practice (3-5). A recent randomized trial also supports the evaluation of thin-catheter MIST as a lung-protective surfactant strategy in very preterm infants (6). Current respiratory management strategies combine early non-invasive support with selective surfactant administration via a thin catheter, aiming to avoid endotracheal intubation and minimize exposure to IMV (2,7). More recent strategies aim to preserve the benefits of surfactant while avoiding the lung injury associated with intubation and positive-pressure ventilation through an endotracheal tube.
Nasal continuous positive airway pressure (NCPAP) is a well-established first-line mode of non-invasive respiratory support for spontaneously breathing preterm infants with RDS (2,8). However, NCPAP failure remains common in very preterm infants, particularly in those with lower gestational age, lower birth weight, severe RDS, or higher oxygen requirement (9,10). Nasal intermittent positive pressure ventilation (NIPPV) delivers intermittent positive-pressure breaths above the positive end-expiratory pressure, thereby augmenting ventilation and supporting functional residual capacity; synchronized NIPPV may also reduce the work of breathing, which is widely used in neonatal respiratory support (11,12). Evidence from randomized trials and systematic reviews suggests that early NIPPV may reduce respiratory failure in comparison to NCPAP in some preterm populations, although the certainty and magnitude of benefit vary across gestational-age groups and clinical contexts (13).
Whether NIPPV provides an additional benefit over NCPAP when both modalities are combined with MIST remains uncertain. A randomized trial comparing NCPAP and NIPPV within a minimally invasive surfactant approach did not fully answer this question, and real-world practice may be influenced by clinician selection of NIPPV for smaller and clinically more vulnerable infants (14,15). Evidence on MIST delivered under NIPPV is also limited and has mainly addressed comparisons with INSURE rather than providing a direct comparison between initial NIPPV and NCPAP (5). Therefore, we performed a retrospective real-world cohort study to compare NIPPV and NCPAP as initial respiratory support during MIST in preterm infants with RDS, with the primary outcome measure of IMV within the first 72 h of life. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0716/rc).
Methods
Study design and setting
This retrospective observational cohort study was conducted in the Level III Neonatal Intensive Care Unit of Dongguan Maternal and Child Health Hospital. Medical records of eligible preterm infants admitted between January 2021 and January 2025 were reviewed. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Institutional Ethics Committee of Dongguan Maternal and Child Health Hospital (2024-152). The requirement for informed consent was waived because this was a retrospective observational study using de-identified data and thus posed minimal risk to participants.
Participants
Infants were included if they were born at <37 weeks of gestation, had a clinical diagnosis of RDS, received exogenous surfactant via MIST within 6 h after birth, and had complete clinical records available for analysis. Infants were excluded if they were intubated at birth, received surfactant using the INSURE technique, had major congenital anomalies, had treatment withdrawn within 24 h after birth with insufficient outcome data, or had incomplete records. A study flow diagram is shown in Figure 1.
Figure 1.
Study flow diagram. NCPAP, nasal continuous positive airway pressure; NIPPV, nasal intermittent positive pressure ventilation; RDS, respiratory distress syndrome.
RDS was diagnosed by the attending neonatal team based on the need for supplemental oxygen and/or non-invasive respiratory support, clinical signs of respiratory distress such as tachypnea, retractions, grunting, and compatible chest radiographic findings when obtained.
Initial respiratory support
Infants were grouped in this analysis according to the initial mode of non-invasive respiratory support selected by the clinical team: NIPPV or NCPAP. NIPPV was initiated with a peak inspiratory pressure of 12–15 cmH2O, positive end-expiratory pressure (PEEP) of 5–6 cmH2O, and a respiratory rate of approximately 30 breaths/min; FiO2 was adjusted to maintain a target oxygen saturation of 90–95%. NCPAP was initiated with a PEEP of 5–6 cmH2O, and FiO2 was titrated to the same oxygen-saturation target. Short binasal prongs (Fisher & Paykel Healthcare Ltd, Auckland, New Zealand) were used as the interface for both modalities.
Surfactant treatment was considered when the infant had worsening RDS with FiO2 >0.30 on CPAP/NIPPV pressure of at least 6 cmH2O, or when clinical and radiographic findings supported persistent surfactant deficiency, consistent with current RDS guidance (16).
MIST procedure and surfactant administration
The MIST procedure was performed in the NICU by two trained neonatologists with assistance from a nurse. Before the procedure, infants continued to receive the assigned non-invasive respiratory support and were positioned in the sniffing position. Under direct laryngoscopy, a 5-Fr feeding tube was advanced through the vocal cords to the desired depth, estimated using the local NICU formula of body weight in kilograms plus 6 cm. After catheter advancement, the laryngoscope was removed, and surfactant was administered slowly through the catheter while non-invasive respiratory support continued. The catheter was removed after the full dose was delivered.
The surfactant administered was Poractant alfa (Curosurf; Chiesi Farmaceutici, Parma, Italy) at 200 mg/kg, or bovine surfactant (Calf Pulmonary Surfactant for Injection; China Resources Double-Crane Pharmaceutical Co., Ltd., China) at 100 mg/kg, according to institutional availability and physician choice. A second surfactant dose was administered using the same minimally invasive approach if the infant continued to require FiO2 >0.30 at 6 h after the initial dose or if chest radiography showed deterioration consistent with persistent RDS.
Criteria for non-invasive support failure
Failure of non-invasive respiratory support was defined by prespecified clinical criteria prompting endotracheal intubation and IMV. For NIPPV, intubation was considered for persistent respiratory acidosis (pH <7.25 with PaCO2 >60 mmHg), recurrent apnea not responsive to non-invasive support, persistent oxygen/pressure requirement of FiO2 >0.40, peak inspiratory pressure >25 cmH2O, or PEEP >6 cmH2O. For NCPAP, intubation was considered for FiO2 >0.40 and PEEP >8 cmH2O despite optimized non-invasive support, for clinically significant apnea, or respiratory acidosis.
Outcomes and definitions
The primary outcome was the need for IMV within the first 72 h of life (17). Secondary outcomes included BPD, moderate or severe BPD, retinopathy of prematurity (ROP), ROP requiring surgical treatment, necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), hemodynamically significant patent ductus arteriosus (hsPDA), sepsis, pneumothorax, repeat surfactant treatment, surfactant dosage, duration of IMV, duration of non-invasive ventilation, length of hospital stay, and blood gas parameters both before and after surfactant administration.
BPD was defined as the need for supplemental oxygen or respiratory support at 36 weeks postmenstrual age among infants who survived to discharge, and moderate or severe BPD was classified according to respiratory-support requirement at 36 weeks postmenstrual age (18). NEC was defined as modified Bell stage II or higher. Other neonatal morbidities were recorded according to diagnoses documented in the medical records using institutional protocols consistent with standard neonatal practice.
Statistical analysis
Continuous variables are presented as mean ± standard deviation or median (interquartile range), as appropriate. Categorical variables are presented as numbers and percentages. Between-group comparisons were performed using the independent-samples t-test or Mann-Whitney U test for continuous variables and the chi-square test or Fisher’s exact test for categorical variables. Unadjusted risk ratios (RRs) and 95% confidence intervals (CIs) were calculated for categorical outcomes, as appropriate.
The primary outcome was further examined using binary logistic regression adjusted for gestational age and birth weight. Because treatment allocation was not randomized, inverse probability of treatment weighting (IPTW) based on gestational age and birth weight was used as an exploratory sensitivity analysis to reduce confounding by baseline immaturity. Prespecified subgroup analyses were conducted by gestational-age strata (<28 weeks, 28 to 31+6 weeks, 32 to 33+6 weeks, and ≥34 weeks). A two-sided P value <0.05 was considered statistically significant. Statistical analyses were performed using SPSS version 26.0 (IBM Corp., Armonk, NY, USA).
Results
Study population and baseline characteristics
Among 967 screened preterm infants with RDS requiring surfactant, 300 infants met the eligibility criteria and were included in the analysis. The NIPPV group contained 170 infants, and the NCPAP group contained 130 infants (Figure 1).
Baseline characteristics are shown in Table 1. Infants in the NIPPV group had significantly lower gestational age than those in the NCPAP group (31.37±2.09 vs. 33.51±1.73 weeks, P<0.001) and lower birth weight (1.60±0.45 vs. 1.99±0.47 kg, P<0.001). Antenatal corticosteroid exposure was numerically higher in the NIPPV group but the difference was not statistically significant based on the tabulated counts. Maternal age, antenatal complications, sex, delivery mode, and multigravidity did not differ significantly between groups.
Table 1. Baseline characteristics of enrolled infants.
| Variable | NIPPV (n=170) | NCPAP (n=130) | Statistic | P value |
|---|---|---|---|---|
| Maternal characteristics | ||||
| Maternal age, years | 31.82±5.51 | 31.46±5.70 | t=0.545 | 0.59 |
| Gestational hypertensive disorders | 21 (12.4) | 19 (14.6) | χ2=0.326 | 0.57 |
| Gestational diabetes | 49 (28.8) | 29 (22.3) | χ2=1.626 | 0.20 |
| Chorioamnionitis | 34 (20.0) | 19 (14.6) | χ2=1.468 | 0.23 |
| Premature rupture of membranes >18 h | 47 (27.6) | 28 (21.5) | χ2=1.466 | 0.23 |
| Placenta previa | 16 (9.4) | 15 (11.5) | χ2=0.360 | 0.55 |
| Amniotic fluid contamination | 7 (4.1) | 7 (5.4) | χ2=0.266 | 0.61 |
| Caesarean delivery | 133 (78.2) | 107 (82.3) | χ2=0.764 | 0.38 |
| Neonatal baseline variables | ||||
| Gestational age, weeks | 31.37±2.09 | 33.51±1.73 | t=7.281 | <0.001 |
| Birth weight, kg | 1.60±0.45 | 1.99±0.47 | t=9.422 | <0.001 |
| Male sex | 101 (59.4) | 74 (56.9) | χ2=0.188 | 0.67 |
| Antenatal corticosteroids | 126 (74.1) | 84 (64.6) | χ2=3.167 | 0.08 |
| Multigravida | 42 (24.7) | 35 (26.9) | χ2=0.190 | 0.66 |
Data are presented as n (%) or mean ± SD. Categorical variables were compared using chi-squared tests unless otherwise indicated. NCPAP, nasal continuous positive airway pressure; NIPPV, nasal intermittent positive pressure ventilation; SD, standard deviation.
Primary outcome
The primary and secondary outcomes are summarized in Table 2. IMV within the first 72 h of life occurred in 27.1% of infants in the NIPPV group and 18.5% of those in the NCPAP group. This difference was not statistically significant in the unadjusted analysis (RR, 1.47; 95% CI: 0.95–2.27; P=0.08).
Table 2. Primary and secondary outcomes.
| Outcome | NIPPV (n=170) | NCPAP (n=130) | Effect estimate (95% CI) | P value |
|---|---|---|---|---|
| Primary outcome | ||||
| IMV within 72 h | 46 (27.1) | 24 (18.5) | RR 1.47 (0.95–2.27) | 0.08 |
| IMV within 72 h, adjusted for GA and BW | – | – | OR 0.605 (0.32–1.14) | 0.12 |
| IMV within 72 h, IPTW analysis | – | – | – | 0.10 |
| Secondary outcomes | ||||
| BPD | 29 (17.1) | 4 (3.1) | RR 5.54 (2.00–15.38) | <0.001 |
| Moderate or severe BPD | 4 (2.4) | 2 (1.5) | RR 1.53 (0.28–8.22) | 0.70† |
| ROP | 31 (18.2) | 12 (9.2) | RR 1.98 (1.06–3.69) | 0.03 |
| ROP requiring surgical treatment | 2 (1.2) | 3 (2.3) | RR 0.51 (0.09–3.01) | 0.66† |
| Second dose of surfactant | 6 (3.5) | 3 (2.3) | RR 1.53 (0.39–6.00) | 0.74† |
| IVH | 24 (14.1) | 20 (15.4) | RR 0.92 (0.53–1.59) | 0.76 |
| hsPDA | 51 (30.0) | 39 (30.0) | RR 1.00 (0.71–1.42) | >0.99 |
| NEC stage II or higher | 3 (1.8) | 1 (0.8) | RR 2.29 (0.24–21.80) | 0.64† |
| PVL | 3 (1.8) | 1 (0.8) | RR 2.29 (0.24–21.80) | 0.64† |
| Sepsis | 11 (6.5) | 6 (4.6) | RR 1.40 (0.53–3.69) | 0.49 |
| Pneumothorax | 5 (2.9) | 4 (3.1) | RR 0.96 (0.26–3.49) | >0.99† |
| Surfactant dose, mg | 184.09±66.32 | 193.57±55.61 | – | 0.23 |
| Time of surfactant administration, h | 1 [1–1] | 1 [1–1] | – | 0.70 |
| Invasive ventilation duration, days | 0 [0–2] | 0 [0–0] | – | 0.09 |
| Non-invasive ventilation duration, days | 10 [6–18] | 6 [4–9] | – | <0.001 |
| Hospital stay, days | 32 [19–47] | 17 [12–29] | – | <0.001 |
Data are presented as n (%), median [interquartile range] or mean ± SD. †, Fisher’s exact test. BPD, bronchopulmonary dysplasia; BW, birth weight; CI, confidence interval; GA, gestational age; hsPDA, hemodynamically significant patent ductus arteriosus; IMV, invasive mechanical ventilation; IPTW, inverse probability of treatment weighting; IVH, intraventricular hemorrhage; NCPAP, nasal continuous positive airway pressure; NEC, necrotizing enterocolitis; NIPPV, nasal intermittent positive pressure ventilation; OR, odds ratio; PVL, periventricular leukomalacia; ROP, retinopathy of prematurity; RR, unadjusted risk ratio; SD, standard deviation.
After adjustment for gestational age and birth weight, the association between initial respiratory-support mode and IMV within 72 h was not statistically significant (adjusted odds ratio, 0.605; 95% CI: 0.32–1.14; P=0.12). The IPTW sensitivity analysis yielded a similar result (P=0.10). In the gestational-age subgroup analyses, the primary outcome did not differ significantly between NIPPV and NCPAP in any stratum (Table 3).
Table 3. Gestational-age subgroup analyses of the primary outcome.
| Gestational-age stratum | Variable/outcome | NIPPV | NCPAP | Statistic/effect | Pvalue |
|---|---|---|---|---|---|
| <28 weeks | N=5 | N=2 | |||
| Gestational age, weeks | 27.44±0.26 | 26.55±0.21 | t=−4.225 | 0.008 | |
| Birth weight, kg | 1.15±0.13 | 0.88±0.07 | t=−2.664 | 0.045 | |
| IMV within 72 h | 3 (60.0) | 0 (0.0) | Not estimable | 0.43† | |
| 28 to 31+6 weeks | N=94 | N=14 | |||
| Gestational age, weeks | 30.02±1.10 | 30.86±0.68 | t=3.882 | 0.001 | |
| Birth weight, kg | 1.35±0.24 | 1.46±0.32 | t=1.598 | 0.11 | |
| IMV within 72 h | 28 (29.8) | 2 (14.3) | RR 2.09 | 0.34† | |
| 32 to 33+6 weeks | N=44 | N=57 | |||
| Gestational age, weeks | 32.79±0.59 | 33.02±0.61 | t=1.915 | 0.06 | |
| Birth weight, kg | 1.76±0.30 | 1.85±0.35 | t=1.376 | 0.17 | |
| IMV within 72 h | 7 (15.9) | 7 (12.3) | RR 1.30 | 0.60 | |
| ≥34 weeks | N=27 | N=57 | |||
| Gestational age, weeks | 34.50±0.67 | 34.89±0.85 | t=2.294 | 0.03 | |
| Birth weight, kg | 2.29±0.42 | 2.29±0.37 | t=0.089 | 0.93 | |
| IMV within 72 h | 8 (29.6) | 15 (26.3) | RR 1.13 | 0.75 |
Data are presented as n (%) or mean ± SD. †, Fisher’s exact test. Effect estimates in the small subgroups should be interpreted cautiously because of limited sample size. IMV, invasive mechanical ventilation; NCPAP, nasal continuous positive airway pressure; NIPPV, nasal intermittent positive pressure ventilation; RR, unadjusted risk ratio; SD, standard deviation.
Secondary outcomes
In the unadjusted comparisons, BPD (RR, 5.54; 95% CI: 2.00–15.38; P<0.001) and ROP (RR, 1.98; 95% CI: 1.06–3.69; P=0.03) were more frequent in the NIPPV group than in the NCPAP group. However, moderate or severe BPD occurred at low rates in both groups (RR, 1.53; 95% CI: 0.28–8.22; P=0.70), and ROP requiring surgical treatment was also uncommon (RR, 0.51; 95% CI: 0.09–3.01; P=0.66). Other major short-term morbidities, including IVH, hsPDA, NEC stage II or higher, PVL, sepsis, and pneumothorax, were similar between groups.
Repeat surfactant treatment and surfactant dosage did not differ significantly between the two groups. The NIPPV group required longer non-invasive ventilation [median, 10 (6–18) vs. 6 (4–9) days; P<0.001] and had a significantly longer hospital stay [median, 32 (19–47) vs. 17 (12–29) days; P<0.001]. These unadjusted differences should be interpreted in the context of the lower gestational age and birth weight of infants selected for NIPPV.
Blood gas changes
Blood gas variables before and after surfactant administration are shown in Table 4. Before surfactant treatment, PCO2 was significantly higher in the NIPPV group than in the NCPAP group (47.81±11.80 vs. 44.95±9.92 mmHg, P=0.03), suggesting greater baseline ventilatory impairment. Other pre-treatment blood gas parameters were not significantly different between groups. After surfactant administration, none of the measured blood gas variables differed significantly between the NIPPV and NCPAP groups. Both groups showed a numerical increase in pH and a decrease in PCO₂ after surfactant administration (pH: P=0.85; PCO2: P=0.97).
Table 4. Blood gas parameters before and after surfactant administration.
| Variable | NIPPV | NCPAP | Statistic | P value |
|---|---|---|---|---|
| Before surfactant | ||||
| pH | 7.30±0.09 | 7.32±0.07 | T/Z=1.471 | 0.14 |
| PCO2, mmHg | 47.81±11.80 | 44.95±9.92 | T/Z=2.134 | 0.03 |
| PO2, mmHg | 113.53±42.20 | 119.88±66.99 | T/Z=0.384 | 0.70 |
| Base excess, mmol/L | −3.81±2.52 | −3.82±2.23 | T/Z=0.068 | 0.95 |
| Lactate, mmol/L | 1.70±0.91 | 1.97±1.69 | T/Z=0.510 | 0.61 |
| After surfactant | ||||
| pH | 7.38±0.09 | 7.38±0.09 | T/Z=0.191 | 0.85 |
| PCO2, mmHg | 38.18±10.44 | 38.11±11.17 | T/Z=0.042 | 0.97 |
| PO2, mmHg | 112.81±37.84 | 127.48±64.37 | T/Z=1.021 | 0.31 |
| Base excess, mmol/L | −2.54±1.94 | −2.49±2.20 | T/Z=0.148 | 0.88 |
| Lactate, mmol/L | 2.00±0.91 | 2.16±1.56 | T/Z=0.932 | 0.35 |
Data are presented as mean ± SD. NCPAP, nasal continuous positive airway pressure; NIPPV, nasal intermittent positive pressure ventilation; PCO2, partial pressure of carbon dioxide; PO2, partial pressure of oxygen; SD, standard deviation.
Discussion
In this retrospective, real-world cohort study of preterm infants with RDS treated with MIST, initial NIPPV and NCPAP were associated with no statistically significant difference in the need for IMV within the first 72 h of life after adjustment for gestational age and birth weight. The unadjusted IMV rate was numerically higher in the NIPPV group, but this group consisted of substantially more immature infants with lower birth weight. After adjustment, the point estimate shifted toward a possible protective association with NIPPV, although the confidence interval was wide and crossed the null. These findings should therefore be interpreted as evidence of comparable short-term effectiveness within the limits of an observational design, rather than proof of superiority or non-inferiority.
The results of this study are biologically plausible and clinically important. NCPAP provides a continuous distending pressure that helps maintain functional residual capacity and is widely used as first-line support for preterm RDS (16,19). NIPPV adds intermittent positive-pressure inflations above baseline PEEP and may improve minute ventilation and reduce apnea and the work of breathing (20). Evidence from systematic reviews and randomized trials suggests that NIPPV can reduce respiratory failure or intubation in selected preterm populations, and the certainty of benefit varies by gestational age, synchronization, device characteristics, timing of use, and surfactant strategy (13,21-24). Our data specifically address a real-world MIST setting, in which both groups received a lung-protective surfactant strategy and surfactant-related confounding was minimized.
Direct evidence comparing NIPPV and NCPAP during MIST is limited. Oncel et al. evaluated these modalities within the setting of using a minimally invasive surfactant approach in a randomized trial, while Huang et al. provided more recent, real-world evidence from infants treated with MIST and non-invasive ventilation (14,15). The present cohort adds to this literature by focusing on IMV within 72 h, applying adjustment for major baseline imbalances, and presenting gestational-age subgroup analyses. The absence of a statistically significant difference across gestational-age strata suggests that, in routine practice, both strategies can be used as initial support during MIST when close monitoring and clear intubation criteria are in place.
The higher unadjusted rates of BPD and ROP in the NIPPV group are most likely explained by baseline immaturity rather than the ventilation mode itself. Lower gestational age and birth weight are established risk factors for both BPD and ROP, while prolonged mechanical ventilation is particularly associated with BPD and may also reflect greater illness severity and a more prolonged clinical course (25-27). In the present study, moderate or severe BPD and ROP requiring surgical treatment did not differ significantly between groups. Further, major complications such as NEC, IVH, hsPDA, sepsis, and pneumothorax were comparable. These findings support the short-term safety of both NIPPV-MIST and NCPAP-MIST strategies, although causality cannot be inferred.
Blood gas findings further support comparable post-surfactant stabilization. Before surfactant administration, infants in the NIPPV group had higher PCO2, consistent with greater baseline respiratory compromise. After MIST, both PCO2 and pH were similar between groups, and both groups showed changes consistent with improved ventilation. This pattern aligns with the physiological rationale of surfactant therapy, which improves alveolar stability and lung compliance and may reduce ventilation-perfusion mismatch when delivered while maintaining spontaneous breathing.
Several limitations must be acknowledged. First, the retrospective single-center design introduces selection bias, because clinicians may have preferentially chosen NIPPV for more immature or clinically unstable infants. Second, gestational age and birth weight were markedly imbalanced between groups. Although multivariable adjustment, IPTW, and subgroup analyses were performed, residual confounding remains possible, particularly from variables such as illness severity, antenatal corticosteroid exposure, radiographic RDS grade, and early oxygen requirement. Third, the subgroup analyses, especially among infants <28 weeks, were statistically underpowered. Fourth, long-term respiratory and neurodevelopmental outcomes were not available. Finally, synchronized versus non-synchronized NIPPV and device-specific factors were not analyzed, which may influence clinical effectiveness.
Conclusions
In conclusion, among preterm infants with RDS treated with MIST, initial NIPPV and NCPAP were associated with no statistically significant difference in IMV within 72 h after adjustment for gestational age and birth weight. NIPPV appears to be a feasible alternative to NCPAP in clinical practice, especially when used within a protocolized MIST pathway. However, because this study was observational and not designed as a non-inferiority trial, larger multicenter randomized studies with prespecified gestational-age stratification and standardized ventilation protocols are needed to determine whether NIPPV offers additional benefit over NCPAP in reducing ventilation failure or improving longer-term outcomes.
Supplementary
The article’s supplementary files as
Acknowledgments
We thank Professor Jie Yang from Southern Medical University for language editing and constructive comments on the manuscript. We also thank Medjaden Inc. for scientific editing of this manuscript.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Institutional Ethics Committee of Dongguan Maternal and Child Health Hospital (2024-152). The requirement for informed consent was waived because this was a retrospective observational study using de-identified data and thus posed minimal risk to participants.
Footnotes
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0716/rc
Funding: None.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0716/coif). The authors have no conflicts of interest to declare.
Data Sharing Statement
Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0716/dss
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