PROJECT SUMMARY This study is designed to answer one of the fundamental gaps in knowledge in the resuscitation of preterm infants at birth: What is the optimal target oxygen saturation (SpO2) range that increases survival without long- term morbidities? Oxygen (O2) is routinely used for the stabilization of preterm infants in the delivery room (DR), but its use is linked with mortality and several morbidities including bronchopulmonary dysplasia (BPD). To balance the need to give sufficient O2 to correct hypoxia and avoid excess O2, the neonatal resuscitation program (NRP) recommends initiating preterm resuscitation with low (≤ 30%) inspired O2 concentration (FiO2) and subsequent titration to achieve a specified target SpO2 range. These SpO2 targets are based on approximated 50th percentile SpO2 (Sat50) observed in healthy term infants. However, the optimal SpO2 targets remain undefined in the preterm infants. Recent data suggest that the inability to achieve SpO2 of 80% by five minutes is associated with intraventricular hemorrhage (IVH) and mortality. These studies raise concern that current SpO2 targets (Sat50) may be too low resulting in persistence of high pulmonary vascular resistance, respiratory failure and mortality. Preliminary data from my NICHD K23 funded pilot randomized controlled trial (RCT) of 75 preterm infants <31 weeks gestational age (GA) showed that infants randomized to 75th percentile SpO2 goals (Sat75) had a lower incidence of SpO2 <80% at five minutes in the DR compared to infants randomized to 50th percentile SpO2 goals (Sat50). In addition, Sat75 infants had less oxidative stress at one hour after birth, needed less respiratory support on admission, had less pulmonary hypertension and had higher survival without BPD. We hypothesize that delivery room resuscitation of preterm infants < 31 weeks GA with Sat75 targets compared to Sat50 targets will increase survival without BPD by 36 weeks’ postmenstrual age (PMA). We plan to conduct a multicenter RCT of Sat75 versus Sat50 powered for survival without BPD. We will randomize 772 infants, 230/7- 306/7 weeks’ GA, to Sat75 (intervention) or Sat50 (control). Except for the SpO2 targets, all resuscitations will follow NRP guidelines including an initial FiO2 of 0.3. In Aim 1, we will determine whether targeting Sat75 compared to Sat50 increases survival without BPD. In addition, we will compare the rates of other major morbidities such as IVH. In Aim 2, we will determine whether targeting Sat75 compared to Sat50 increases survival without neurodevelopmental impairment at 2 years of age. In Aim 3, we will determine whether targeting Sat75 compared to Sat50 decreases oxidative stress. We will conduct a sub-study of 220 infants enrolled from a single site to measure 8-iso-PGF2α and 8-OHdG in cord blood and blood samples collected at 1 and 24 hours after birth. The new understanding gained from this trial has the potential to modify neonatal resuscitation practice and improve neonat...