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ObjectiveMeasuring exhaled carbon dioxide (ECO2) during non-invasive ventilation at birth may provide information about lung aeration. However, the International Liaison Committee on Resuscitation (ILCOR) only recommends ECO2detection for confirming endotracheal tube placement. ILCOR has therefore prioritised a research question that needs to be urgently evaluated: ‘In newborn infants receiving intermittent positive pressure ventilation by any non-invasive interface at birth, does the use of an ECO2monitor in addition to clinical assessment, pulse oximetry and/or ECG, compared with clinical assessment, pulse oximetry and/or ECG only, decrease endotracheal intubation in the delivery room, improve response to resuscitation, improve survival or reduce morbidity?’.DesignSystematic review of randomised and non-randomised studies identified by Ovid MEDLINE, Embase and Cochrane CENTRAL search until 1 August 2022.SettingDelivery room.PatientsNewborn infants receiving non-invasive ventilation at birth.InterventionECO2measurement plus routine assessment compared with routine assessment alone.Main outcome measuresEndotracheal intubation in the delivery room, response to resuscitation, survival and morbidity.ResultsAmong 2370 articles, 23 were included; however, none had a relevant control group. Although studies indicated that the absence of ECO2may signify airway obstruction and ECO2detection may precede a heart rate increase in adequately ventilated infants, they did not directly address the research question.ConclusionsEvidence to support the use of an ECO2monitor to guide non-invasive positive pressure ventilation at birth is lacking. More research on the effectiveness of ECO2measurement in addition to routine assessment during non-invasive ventilation of newborn infants at birth is needed.PROSPERO registration numberCRD42022344849.