MANUSCRIPT CITATION

Lipp R, Beltempo M, Lodha A, Weisz D, McKanna J, Matthews I, Ricci MF, Hicks M, Benlamri A, Mukerji A, et al. Noninvasive respiratory support or intubation during stabilization after birth and neonatal and neurodevelopmental outcomes in infants born preterm at 23-25 weeks of gestation. J Pediatr. 2025;276:114270. doi:10.1016/j.jpeds.2024.114270.

REVIEWED BY

Name, Title: N Rao1, H Gowda2
Institution: 1. Independent Researcher. 2. University Hospitals of Birmingham NHS Trust.
Email: Narasimha.rao@nhs.net

TYPE OF INVESTIGATION

Choose from one of the following: Treatment.

QUESTION

In preterm infants born at 23-25 weeks of gestation, does non-invasive respiratory support (NRS) during the first 30 minutes after birth, compared to tracheal intubation (TI), reduce the risk of severe brain injury or death before NICU discharge and improve neurodevelopmental outcomes at 18-24 months of corrected age?

METHODS

• Design: Retrospective

• Allocation: Non-randomised; observational design with infants allocated into two groups based on exposure.
o NRS Group: Successfully managed with non-invasive respiratory support (NRS) for at least 30 minutes after birth.
o TI Group: Tracheal intubation (TI) within the first 30 minutes after birth.
o Propensity score matching was used to adjust for confounding.

• Blinding: Not applicable due to retrospective study design.

• Follow-up period:
o NICU stay for severe brain injury or death before discharge.
o Follow-up at 18-24 months corrected age for neurodevelopmental outcomes amongst survivors.

• Setting: Canadian tertiary neonatal intensive care units participating in the Canadian Neonatal Network.

• Patients:
o Preterm infants born at 23-25 weeks of gestation and admitted to CNN NICUs.
o Inclusion Criteria:
 Gestational age between 23 0/7 and 25 6/7 weeks.
 Admitted to NICU at CNN centres between January 2010 and December 2019.
o Exclusion Criteria:
 Major congenital anomalies or chromosomal abnormalities.
 Received palliative care at birth.
 Extensive resuscitation (chest compressions ≥30 seconds or IV/endotracheal epinephrine).
 Apgar score ≤1 at 1 minute or ≤3 at 5 minutes.
 Out born infants.

• Intervention:

o NRS Group: Non-invasive respiratory support (NRS), such as CPAP, nasal intermittent positive pressure ventilation, or high-flow nasal cannula ≥2 L/min.
o TI Group: Early tracheal intubation (TI) within the first 30 minutes after birth.

• Outcomes:

Primary Outcomes:
a. Severe brain injury (sBI) or death in NICU before discharge. sBI defined as intraventricular haemorrhage grade 3/4 or periventricular leukomalacia.
b. Significant neurodevelopmental impairment (sNDI) at 18-24 months corrected age. sNDI defined as:
• Bayley-III score <70 in any domain. • Cerebral palsy with GMFCS level ≥3. • Bilateral blindness. • Hearing loss requiring amplification. Secondary Outcomes: • NICU outcomes: • Late-onset sepsis. • Necrotizing enterocolitis (Bell’s stage ≥2). • Bronchopulmonary dysplasia (BPD). • Severe retinopathy of prematurity. • Follow-up outcomes: • Any neurodevelopmental impairment (NDI). • Use of aids at home (oxygen, feeding tubes, CPAP, etc.). • Analysis and Sample Size: Statistical Analysis: – Descriptive statistics for baseline characteristics. – Logistic regression models adjusted for confounders (gestational age, antenatal steroids, SGA status, sex, and centre). – Propensity score matching with caliper width of 0.1 SD to balance baseline variables between NRS and TI groups. – Sensitivity analyses excluding sicker infants (Apgar score >5 at 5 minutes).

Sample Size:
– Total NICU cohort: 3,130 infants (NRS = 1,118; TI = 2,012).
– Follow-up sub-cohort: 1,488 infants (NRS = 551; TI = 937).

MAIN RESULTS

This study demonstrated that the use of non-invasive respiratory support (NRS) during the first 30 minutes of stabilization in preterm infants born at 23-25 weeks of gestation was associated with significantly lower odds of severe brain injury (sBI) or death before NICU discharge compared to early tracheal intubation (TI) (adjusted odds ratio 0.74; 95% CI 0.60–0.91). However, no significant differences were observed in long-term neurodevelopmental impairment (sNDI) at 18-24 months corrected age among survivors after adjusting for confounders (OR 0.78; 95% CI 0.58–1.05).

CONCLUSION

The study concluded that non-invasive respiratory support (NRS) during the initial stabilization of preterm infants born at 23-25 weeks’ gestation was associated with lower odds of severe brain injury or death before NICU discharge. However, NRS did not significantly impact long-term neurodevelopmental outcomes at 18-24 months corrected age. While NRS shows promise in reducing immediate neonatal morbidities, further prospective studies are needed to refine its application and evaluate its broader impact on neurodevelopment.

COMMENTARY

With improved care translating into increased survival rates of extremely preterm infants, the respiratory morbidity rates have remained constant (1,2). The focus of research and practice has shifted towards minimising the duration of invasive ventilation to enhance pulmonary and neurodevelopmental outcomes in this vulnerable population (3,4).

 

Growing evidence links invasive ventilation at birth to higher mortality and bronchopulmonary dysplasia rates, prompting a shift towards optimising primary respiratory support and avoiding invasive ventilation in the initial hours of life to improve outcomes (5).

 

Deferring the commencement of invasive mechanical ventilation has a role in limiting the total duration of the same as the primary respiratory support in extremely preterm infants has been associated with improved outcomes, particularly a reduction in bronchopulmonary dysplasia (BPD) (6,7).

 

Utilisation of non-invasive respiratory support has been increasingly taken up in clinical practice and has found its place in international guidelines (8). But these practice recommendations are based on low representative data(9). Infants born <25 weeks of gestation are not well-represented in the evidence used to develop major clinical guidelines for infants born extremely preterm. Therefore, this study by Lipp et al finds relevance in representing a large national cohort of extreme preterm newborn infants.

 

Lipp et al, a retrospective cohort study from the Canadian neonatal network of infants born at 23 1/7 to 25 6/7 weeks of gestation. With well-defined objective measures, primary and secondary outcomes find significance in clinical care. Use of propensity score matching with strict inclusion and exclusion criteria ensures minimisation of bias. Infants in this study have been followed-up until 18-24 months corrected age and the use of standardised neurodevelopmental tool ensures applicability and reliability of results.

 

Gestation age and birth weight were significantly lower in the Tracheal Intubation (TI) compared to the non-invasive respiratory support (NRS) group. Some of the perinatal optimisation to improve outcomes like antenatal steroids, delayed cord clamping and magnesium sulphate were significantly lower in TI group (p<0.01).

 

However, owing to the retrospective observational nature of this study, there is a risk of residual confounding and bias from factors such as a clinician preference and severity of illness influencing stabilisation strategy. The follow-up rates were 60-62%, which may misidentify rates of neurodevelopmental impairment between the two cohorts. The generalisability of the results may be limited because very sick infants were excluded and because of differences in clinical practices and/ or resource availability. Factors such as provider expertise, reasons for intubation and stabilisation, which could influence outcomes, were not captured. Retrospective data collected over 10 years, during which the temporal change in clinical practices and technologies likely evolved, could potentially influence outcomes.

 

This study should inform clinicians that with careful selection of candidates, NRS is a feasible primary respiratory support for extreme preterm infants and that it reduces severe brain injury or mortality without increasing short-term NICU morbidities. However, it does not guarantee better neurodevelopmental outcomes.

 

The study also identifies future research areas, including a prospective randomised controlled trial methodology focusing on severe brain injury and mortality during NICU stays. Determining clinical and physiological predictors of successful NRS stabilisation is crucial for identifying the optimal eligible candidate for NRS.

REFERENCES

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2. Boel L, Banerjee S, Clark M, Greenwood A, Sharma A, Goel N, et al. Temporal trends of care practices, morbidity, and mortality of extremely preterm infants over 10-years in South Wales, UK. Sci Rep [Internet]. 2020 Dec 1 [cited 2025 Jan 28];10(1):18738. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC7603316/

3. Vliegenthart RJS, Van Kaam AH, Aarnoudse-Moens CSH, Van Wassenaer AG, Onland W. Duration of mechanical ventilation and neurodevelopment in preterm infants. Arch Dis Child Fetal Neonatal Ed [Internet]. 2019 Nov 1 [cited 2024 Dec 27];104(6):F631–5. Available from: https://fn.bmj.com/content/104/6/F631

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6. Fischer HS, Bührer C. Avoiding endotracheal ventilation to prevent bronchopulmonary dysplasia: a meta-analysis. Pediatrics [Internet]. 2013 Nov 1 [cited 2024 Dec 27];132(5). Available from: https://pubmed.ncbi.nlm.nih.gov/24144716/
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8. Sweet DG, Carnielli VP, Greisen G, Hallman M, Klebermass-Schrehof K, Ozek E, et al. European Consensus Guidelines on the Management of Respiratory Distress Syndrome: 2022 Update. Neonatology [Internet]. 2023 Mar 1 [cited 2024 Dec 27];120(1):3–23. Available from: https://pubmed.ncbi.nlm.nih.gov/36863329/

9. Peart S, Kahvo M, Alarcon-Martinez T, Hodgson K, Eger SH, Donath S, et al. Clinical Guidelines for Management of Infants Born before 25 Weeks of Gestation: How Representative Is the Current Evidence? J Pediatr [Internet]. 2024 Nov 27 [cited 2024 Dec 27];278:114423. Available from: https://pubmed.ncbi.nlm.nih.gov/39613140/