Oxygen vs Air at Birth for Moderate- to Late-Preterm Infants

Importance: The optimal initial fraction of inspired oxygen (Fio2) for delivery room resuscitation of neonates born at 32 to 35 weeks' gestation is unknown. Objective: To compare outcomes for neonates born at 32 to 35 weeks' gestation when initiating resuscitation with Fio2 0.30 vs 0.21. Design, Setting, and Participants: Unblinded, cluster randomized crossover trial in 26 Australian maternity hospitals, including tertiary, nontertiary, metropolitan, regional, public, and private sites, using a waiver of informed consent. All neonates born at participating sites at 32 to 35 weeks' gestation without known major congenital anomalies who commenced respiratory support within 3 minutes of birth were enrolled from December 2022 to September 2025, with final follow-up in March 2026. Statistical analysis was conducted on October 29, 2025. Intervention: Sites were randomly assigned to provide initial Fio2 of either 0.30 or 0.21 during the first 3 minutes of delivery room respiratory support. Sites crossed over to provide the alternative initial Fio2 halfway through their recruitment period. Main Outcomes and Measures: The primary outcome was ongoing respiratory support when leaving the delivery room. Twelve secondary outcomes evaluated delivery room treatments and respiratory support until discharge. Results: A total of 1818 eligible newborns (mean gestational age, 34.1 weeks; mean birth weight, 2165 g; 44.7% female) were included. Ongoing respiratory support when leaving the delivery room occurred in 700 of 964 newborns (72.6%) randomized to receive Fio2 0.30 and 626 of 854 newborns (73.3%) randomized to receive Fio2 0.21 (risk difference, -0.83 [95% CI, -4.33 to 2.67]). Of the 12 secondary outcomes, 10 were not significantly different between newborns randomized to receive Fio2 0.30 vs 0.21, while 2 were. Newborns randomized to receive Fio2 0.30 were less likely to receive higher levels of support in the delivery room, including noninvasive positive pressure ventilation (606 of 964 [62.9%] vs 560 of 854 [65.6%]), endotracheal or supraglottic airway ventilation (20 of 964 [2.1%] vs 24 of 854 [2.8%]), or cardiac compressions or epinephrine (19 of 964 [2.0%] vs 25 of 854 [2.9%]; proportional odds ratio, 0.70 [95% CI, 0.52-0.95]). Fewer newborns in the Fio2 0.30 group received endotracheal ventilation beyond the delivery room (61 of 959 [6.4%] vs 79 of 852 [9.3%]; risk ratio, 0.69 [95% CI, 0.47-0.91]). Conclusions and Relevance: For neonates born at 32 to 35 weeks' gestation, there was no difference between those commencing resuscitation with Fio2 0.30 vs Fio2 0.21 in the proportion still receiving respiratory support when leaving the delivery room. Trial Registration: anzctr.org.au Identifier: ACTRN12621001267842.