QTc intervals are prolonged in (near)term neonates during therapeutic hypothermia to normalise immediately afterwards

Background: There are anecdotic reports on reversible QTc prolongation during therapeutic hypothermia (TH) for moderate to severe neonatal encephalopathy after asphyxia. As the QTc interval is a relevant biomarker to assess safety during medicine development, a structured search and review on published QTc values to generate reference values is warranted to facilate medicine development in this specific population. Methods: a structured search and literature assessment (PubMed, Embase, Google Scholar) with ‘Newborn/Infant, QT and hypothermia’ was conducted (October 2021). Retrieved individual values were converted to QTc (Bazett) over postnatal age (day 1-7). Results: we retrieved 94 QTc intervals [during TH (n=50, until day 3) or subsequent normothermia (n=44, day 4-7)] in 33 neonates form 6 publications. The median (range) of QTc intervals during TH was 508 (430-678), and 410 (317-540) ms afterwards (difference 98 ms, or +28 ms/°C decrease). Four additional cohorts (without individual QTc intervals) confirmed the pattern and magnitude of the effect of body temperature on the QTc interval. Conclusions: we added a relevant nonmaturational covariate (TH, dose dependent) and generated reference values for the QTc interval in this specific subpopulation. This knowledge on QTc during TH should be considered and integrated in neonatal medicine development.