Delayed Cord Clamping with Oxygen In Extremely Low Gestational Age Infants (DOXIE)

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Background: Current newborn care practice is to delay clamping and cutting the umbilical cord to allow for hemodynamic stabilization. Supported by numerous randomized controlled trials and meta-analyses, delayed cord clamping (DCC) is endorsed by both neonatal and obstetrical governing bodies. Limited oxygenation data on DCC in extremely preterm infants suggests they remain hypoxic immediately after birth. This may be due to differences in how infants transition during DCC. Immediately after delivery, extremely preterm infants attempt to initiate lung aeration and gas exchange. Animal studies have demonstrated that delaying clamping of the umbilical cord until breathing is established avoids adverse cerebral and cardiac hemodynamics, which may reduce bleeding in the brain, including severe intraventricular hemorrhage (sIVH). In a multicenter trial comparing DCC to umbilical cord milking, 76 percent of preterm newborns between 230-276 weeks gestation who received DCC without respiratory support initiated respirations prior to cord clamping, yet still had relative hypoxia demonstrated by a low 5-minute arterial oxygen saturation (SpO2 73 percent (95% CI 71.4, 75.6)). Two recent analyses found that preterm infants with a 5-minute SpO2 < 80 percent were more likely to have sIVH or death. Supplemental oxygen provided during DCC with resultant lung aeration may decrease significant morbidities and death in extremely preterm infants. A pilot study with detailed assessments of hemodynamics and organ function immediately after birth is needed to determine the efficacy and safety of providing 100 percent oxygen during DCC. Design: This randomized double-blinded pilot trial will enroll 140 extremely low gestational age infants (230- 276 weeks gestation) who receive DCC of at least 60 seconds with carefully detailed hemodynamic assessments and simultaneous video recordings. The study will evaluate infants providing continuous positive airway pressure (CPAP) and/or positive pressure ventilation (PPV) by face mask with an inspired fractional oxygen (FiO2) of 1.0 (HI Group) during DCC compared to infants given mask CPAP/PPV with an inspired FiO2 of 0.30 during DCC (LO Group). Due to the nature of the intervention, both arms receive CPAP/PPV with identical cord clamping times and respiratory support, the study can be blinded by covering the oxygen blender, avoiding any postnatal treatment bias. Once the cord is clamped and cut, each infant is resuscitated as per usual protocol (CPAP/PPV with a starting FiO2 0.30) by the clinical team. We will collect physiological parameters from birth through the first 24 hours of life (including detailed breathing assessments from video recordings at birth/ resuscitation suite). If we reduce hypoxia in extremely preterm infants by providing supplemental oxygen during the period of delayed cord clamping, there may be a dramatic reduction in morbidity and mortality. Depending on the findings, results will be used to design a more definitive larger, multicenter R01 trial powered for important clinical outcomes such as severe IVH or death and neurodevelopmental outcomes.