Highlights
- Delivering 100% oxygen by face mask during deferred cord clamping (DCC) significantly increases the proportion of extremely preterm infants achieving target oxygen saturation (≥80%) by 5 minutes of life compared to 30% oxygen.
- High oxygen during DCC does not increase risk of hyperoxemia, severe intraventricular hemorrhage, or early mortality in extremely preterm infants.
- The study provides robust randomized controlled trial evidence supporting modification of current neonatal resuscitation protocols during DCC to reduce early hypoxemia.
- Large multicenter trials remain necessary to assess longer-term survival and neurodevelopmental outcomes associated with 100% oxygen use during DCC.
Background
Extremely preterm infants (born at 22 to 28 weeks of gestation) are at high risk of early hypoxemia due to immature lung function and transitional circulatory changes. Hypoxia in the immediate postnatal period is a critical determinant of mortality and morbidities such as intraventricular hemorrhage (IVH) and bronchopulmonary dysplasia. Deferred cord clamping (DCC), where umbilical cord clamping is delayed by at least 30-60 seconds after birth, has been widely adopted to improve cardiovascular stability and placental transfusion. However, the optimal oxygen concentration to administer during DCC remains uncertain. While 30% oxygen is conventionally used, concerns about hypoxia have led to interest in supplemental 100% oxygen during this period. The balance between reducing early hypoxemia and avoiding hyperoxia-related injury remains a clinical challenge. Prior to 2025, no definitive randomized evidence existed regarding the safety and efficacy of using high oxygen concentrations during DCC in this vulnerable population.
Key Content
Chronological Development of Evidence on Oxygen Use During DCC
Early studies predominantly focused on timing of cord clamping, demonstrating benefits of DCC on hematologic and hemodynamic parameters in preterm infants. Research then expanded to optimal respiratory support during this transitional period. Observational data suggested that maintaining adequate oxygenation immediately after birth improves neonatal outcomes. However, concerns about oxygen toxicity and oxidative stress led to guidelines recommending the lowest effective oxygen concentration, typically around 21-30%.
The randomized clinical trial by Katheria et al. (2025) represents a landmark investigation directly comparing high (100%) versus low (30%) oxygen concentrations administered via face mask during DCC in extremely preterm infants, while all infants received standardized resuscitation post-cord clamping. The trial enrolled 140 infants of mean 26 weeks gestational age across multiple centers, representing a robust and generalizable preterm population.
Study Design and Interventions
This double-blinded randomized trial allocated preterm infants to either 30% or 100% oxygen during DCC, with continuous positive airway pressure or positive pressure ventilation delivered via face mask. A concealed oxygen blender ensured blinding of clinicians. After cord clamping, all infants received resuscitation according to contemporary Neonatal Resuscitation Program guidelines, titrating oxygen based on preductal peripheral oxygen saturation targets.
Primary and Secondary Outcomes
The primary outcome was the proportion of infants achieving peripheral oxygen saturation of at least 80% by 5 minutes of life. Secondary endpoints included the incidence of hyperoxemia, maximum fraction of inspired oxygen (FiO2) during resuscitation, umbilical arterial partial pressure of oxygen, severe intraventricular hemorrhage (grade III-IV), and death before 40 weeks’ postmenstrual age.
Major Findings
Infants receiving 100% oxygen during DCC demonstrated a markedly higher achievement rate of targeted oxygen saturation (69% vs 39%; adjusted OR 3.74, 95% CI 1.80–7.79; P < .001) compared with the 30% oxygen group. Importantly, the absolute risk difference of 0.3 (95% CI 0.26–0.35) indicated a 30% reduction in hypoxemia risk at 5 minutes. There was no significant difference between groups in the maximum median FiO2 used during subsequent resuscitation, or arterial oxygen tension, reassuring regarding the absence of hyperoxemia. No increase in severe IVH or mortality was observed, suggesting safety of the intervention.
Context within Neonatal Resuscitation Guidelines and Prior Research
Current neonatal resuscitation guidelines emphasize avoiding both hypoxia and hyperoxia but have historically lacked evidence on oxygen concentration during DCC. Previous studies focused on immediate initiation of ventilation after DCC to facilitate lung aeration and reduce hypoxemia, yet optimal oxygen levels were undefined. The trial by Katheria et al. directly addresses this gap, demonstrating a clear benefit of 100% oxygen during the DCC window to expedite oxygen saturation without increasing harm. The findings complement earlier work supporting early respiratory support during DCC to improve neonatal stability.
Potential Mechanisms and Physiological Rationales
During DCC, umbilical venous blood continues oxygen exchange, providing some oxygenation. However, extremely preterm lungs are structurally immature and may not adequately oxygenate. Supplemental 100% oxygen may augment oxygen transfer to pulmonary circulation and facilitate more rapid transition to extrauterine oxygenation. The absence of hyperoxemia despite high inspired oxygen is likely due to continued mixing with primarily desaturated umbilical venous blood, which dilutes arterial oxygen content and reduces oxidative stress risk during this period.
Expert Commentary
This trial represents a pivotal addition to the evidence base on neonatal resuscitation, particularly for extremely preterm infants who are vulnerable to hypoxia-related injury. The rigorous randomized, double-blind design strengthens internal validity, and multicenter enrollment enhances external applicability. The statistically robust and clinically meaningful increase in early oxygen saturation achievement supports considering 100% oxygen during DCC as a standard practice modification.
However, limitations include the relatively small sample size for detecting rare adverse outcomes and lack of longer-term neurodevelopmental outcome data. The absence of increased severe IVH or mortality at 40 weeks gestational age is reassuring but not definitive for safety. Given concerns about hyperoxia-induced oxidative injury, further large-scale studies are warranted to confirm long-term safety and efficacy.
Guideline committees may consider these findings as they update neonatal resuscitation protocols, balancing potential benefits against theoretical risks. Mechanistically, the study highlights the importance of synchronizing respiratory support and oxygen delivery with cord clamping physiology to optimize neonatal transition. Future research may explore titration strategies within the first minutes after birth and the role of oxygen delivery in other vulnerable neonatal populations.
Conclusion
The randomized clinical trial by Katheria et al. provides compelling evidence that administering 100% oxygen via face mask during deferred cord clamping significantly reduces early hypoxemia in extremely preterm infants without increasing immediate morbidity. This intervention may improve neonatal stabilization in the critical birth transition phase. Pending confirmation in larger randomized trials assessing survival and neurodevelopmental outcomes, adopting higher inspired oxygen concentrations during DCC represents a promising advance in neonatal resuscitation practice for the most vulnerable preterm infants.
References
- Katheria AC, Ines F, Lee HC, et al. Deferred Cord Clamping With High Oxygen in Extremely Preterm Infants: A Randomized Clinical Trial. JAMA Pediatr. 2025;179(9):971-978. doi:10.1001/jamapediatrics.2025.2128. PMID: 40690234; PMCID: PMC12281397.
- Wyllie J, Bruells CS, Roehr CC, et al. Oxygen therapy during delivery room stabilization of preterm infants: A systematic review. Resuscitation. 2020;146:20-30. PMID: 32211447.
- Rabe H, Draycott TJ, Owen LS, et al. Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes. Cochrane Database Syst Rev. 2021;2021(8):CD003248. PMID: 34369213.
- Wyckoff MH, Aziz K, Escobedo MB, et al. Part 13: Neonatal Resuscitation: 2020 American Heart Association Guidelines Update. Circulation. 2020;142(16_suppl_2):S524-S550. PMID: 33067260.
