Manuscript citation:
Deferred Cord Clamping With High Oxygen in Extremely Preterm Infants: A Randomized Clinical Trial. Katheria et al., JAMA Pediatrics 2025 Sep 1;179(9):971-978. doi: 10.1001/jamapediatrics.2025.2128. PMID 40690234
Reviewed By:
Simone Pratesi
University of Florence
Careggi University Hospital
Florence, Italy
Design:
Double-blinded, multicenter randomized clinical trial.
Allocation: Infants were randomized to receive either 100% oxygen (high oxygen group) or 30% oxygen (low oxygen group) during deferred cord clamping (DCC), using a concealed oxygen blender.
Blinding:
Blinding was maintained for both clinical teams and parents by covering the oxygen blender settings. Treatment assignment was concealed until after randomization.
Follow-up Period: Primary outcomes assessed at 5 minutes of life; exploratory outcomes followed through NICU stay and up to 40 weeks postmenstrual age.
Setting:
Three hospital centers in California: two university hospitals and one private medical center.
Patients (Inclusion/Exclusion Criteria):
Inclusion:
• Infants born at 22 to 28 weeks’ gestational age
• Parental consent obtained before delivery
Exclusion:
• Rupture of membranes before 20 weeks
• Monochorionic twins with twin-to-twin transfusion syndrome
• Placenta accreta
• Major congenital anomalies
Intervention:
During DCC (90 seconds), infants received CPAP or PPV via face mask with either 100% or 30% oxygen. After cord clamping, all infants were resuscitated per standard guidelines starting at 30% oxygen.
Primary Outcome:
Proportion of infants achieving SpO₂ ≥80% by 5 minutes of life
Main Exploratory Outcomes:
• Peripheral oxygen saturation (SpO₂) at 5 minutes
• Heart rate measurements during the first 10 minutes
• Delivery room interventions (intubation, surfactant, epinephrine)
• Cerebral oxygenation and blood pressure in the first 24 hours
• Intraventricular hemorrhage (IVH)
• Mortality before 40 weeks PMA
• Bronchopulmonary dysplasia (BPD)
.
Analysis and Sample Size:
Sample size:140 infants (70 per group);
Power:
80% to detect a 20% absolute a 20% absolute reduction in the incidence of oxygen saturation <80% at 5 minutes after birth
Statistical methods:
Chi-square, Fisher’s exact test, t-test, Mann-Whitney U, logistic regression, generalized estimating equations (GEE)
Patient Follow-up (% Included in Analysis):
100% of randomized infants were included in the intention-to-treat analysis.
MAIN RESULTS:
• 69% of infants in the high oxygen group achieved SpO₂ ≥80% by 5 minutes vs. 39% in the low oxygen group (adjusted OR 3.74; 95% CI, 1.80–7.79; P < .001)
• No significant differences in severe IVH, mortality, or other adverse outcomes
• Time to reach target SpO₂ was shorter in the high oxygen group
• No increase in systemic or cerebral hyperoxia observed
CONCLUSION:
Administering 100% oxygen during DCC significantly reduced early hypoxemia in extremely preterm infants without increasing morbidity. These findings support reconsideration of oxygen strategies during DCC and warrant larger trials to assess long-term outcomes.
COMMENTARY
This is a very interesting and well-designed trial with several strengths. Deferred cord clamping (DCC) for at least 120 seconds is associated with the highest likelihood of reducing mortality in preterm newborns (1). However, such prolonged DCC is feasible only when the newborn does not require respiratory support within the first minute of life.
Recently, three randomized controlled trials have compared resuscitation with an intact cord (lasting 2 to 6 minutes) to either deferred cord clamping (30–60 seconds) or umbilical cord milking (2-4). All three trials failed to show an improvement in the primary outcome. This raises an important question: why does intact cord resuscitation not improve outcomes in preterm infants compared to resuscitation after DCC or milking?
Possible explanations include reduced resuscitation quality at the bedside (with greater hypothermia), technical difficulty and variable expertise (5), and persistent early hypoxia, with low oxygen saturation at 5 minutes of life linked to adverse outcomes in very preterm infants (6).
Recent animal studies provide new physiological insights (7,8). In preterm lambs, brief ventilation with 100% oxygen while the umbilical cord remains intact promotes an increase in pulmonary blood flow without inducing systemic hyperoxia (7). This probably occurs because the newborn reduces oxygen uptake across the placenta, and when oxygen levels exceed fetal needs, the mother effectively acts as an ‘oxygen sink’ (8).
In the current trial, a peripheral oxygen saturation of 80% at 5 minutes was achieved more frequently (69% vs. 39%) when preterm infants were resuscitated on the cord with 100% oxygen for up to 90 seconds, compared to 30 seconds. This may reflect the beneficial role of 100% oxygen in enhancing pulmonary vasodilation and blood flow, as seen in lambs, and potentially in facilitating glottic opening and pulmonary ventilation. However, the similar rates of positive pressure ventilation (PPV) before and after cord clamping, along with comparable intubation rates between the low‑ and high‑oxygen groups, indicate that the beneficial effects of oxygenation on the initiation of spontaneous breathing or glottic opening do not appear to translate into clinical advantages. The two following considerations could at least partially explain this result. The paper fails to indicate how many infants were not breathing after birth, and this subgroup might have benefited more from receiving 100% oxygen. This is a critical consideration, especially since the Vent First trial (2) reported a high proportion (48%) of infants who were not breathing adequately at birth, and this subgroup appeared to benefit more from intact cord resuscitation with 30% oxygen. Moreover, it should be kept in mind that clinicians often underestimate spontaneous breathing and are frequently quick to initiate PPV in preterm infants, which makes it more difficult to detect differences in PPV rates between groups (9).
Administering 100% oxygen with the cord intact improves early oxygenation in preterm infants without increasing the risk of short-term morbidity. Future larger trials on intact cord resuscitation, conducted in centers with established expertise in this procedure, should incorporate the short-term use of 100% oxygen into their study design. This may help demonstrate improved outcomes in infants resuscitated with an intact cord.
REFERENCES
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