OPtimal TIming of antenatal COrticosteroid administration in pregnancies complicated by early-onset fetal growth REstriction (OPTICORE): study protocol of a multicentre, retrospective cohort study.

INTRODUCTION: Early-onset fetal growth restriction (FGR) requires timely, often preterm, delivery to prevent fetal hypoxia causing stillbirth or neurologic impairment. Antenatal corticosteroids (CCS) administration reduces neonatal morbidity and mortality following preterm birth, most effectively when administered within 1 week preceding delivery. Optimal timing of CCS administration is challenging in early-onset FGR, as the exact onset and course of fetal hypoxia are unpredictable. International guidelines do not provide a directive on this topic. In the Netherlands, two timing strategies are commonly practiced: administration of CCS when the umbilical artery shows (A) a pulsatility index above the 95thh centile and (B) absent or reversed end-diastolic velocity (a more progressed disease state). This study aims to (1) use practice variation to compare CCS timing strategies in early-onset FGR on fetal and neonatal outcomes and (2) develop a dynamic tool to predict the time interval in days until delivery, as a novel timing strategy for antenatal CCS in early-onset FGR. METHODS AND ANALYSIS: A multicentre, retrospective cohort study will be performed including pregnancies complicated by early-onset FGR in six tertiary hospitals in the Netherlands in the period between 2012 and 2021 (estimated sample size n=1800). Main exclusion criteria are multiple pregnancies and fetal congenital or genetic abnormalities. Routinely collected data will be extracted from medical charts. Primary outcome for the comparison of the two CCS timing strategies is a composite of perinatal, neonatal and in-hospital mortality. Secondary outcomes include the COSGROVE core outcome set for FGR. A multivariable, mixed-effects model will be used to compare timing strategies on study outcomes. Primary outcome for the dynamic prediction tool is 'days until birth'. ETHICS AND DISSEMINATION: The need for ethical approval was waived by the Ethics Committee (University Medical Center Utrecht). Results will be published in open-access, peer-reviewed journals and disseminated by presentations at scientific conferences. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT05606497.

Pathophysiology of Cerebral Hyperperfusion in Term Neonates With Hypoxic-Ischemic Encephalopathy: A Systematic Review for Future Research.

Worldwide neonatal hypoxic-ischemic encephalopathy (HIE) is a common cause of mortality and neurologic disability, despite the implementation of therapeutic hypothermia treatment. Advances toward new neuroprotective interventions have been limited by incomplete knowledge about secondary injurious processes such as cerebral hyperperfusion commonly observed during the first 1-5 days after asphyxia. Cerebral hyperperfusion is correlated with adverse neurodevelopmental outcome and it is a process that remains poorly understood. In order to provide an overview of the existing knowledge on the pathophysiology and highlight the gaps in current understanding of cerebral hyperperfusion in term animals and neonates with HIE, we performed a systematic research. We included papers scoping for study design, population, number of participants, study technique and relevant findings. Methodological quality was assessed using the checklist for cohort studies from The Joanna Briggs Institute. Out of 2,690 results, 34 studies were included in the final review-all prospective cohort studies. There were 14 studies of high, 17 moderate and 3 of low methodological quality. Data from the literature were analyzed in two main subjects: (1) Hemodynamic Changes subdivided into macro- and microscopic hemodynamic changes, and (2) Endogenous Pathways which was subdivided into N-methyl-D-aspartate/Mitogen activated protein kinase (NDMA/MAPK), Nitric Oxide (NO), prostanoids and other endogenous studies. Cerebral hyperperfusion in term neonates with HIE was found to be present 10-30 min after the hypoxic-ischemic event and was still present around day 10 and up to 1 month after birth. Cerebral hyperperfusion was also characterized by angiogenesis and cerebral vasodilation. Additionally, cerebral vasodilation was mediated by endogenous pathways such as MAPK through urokinase Plasminogen Activator (uPA), by neuronal NO synthase following NMDA and by prostanoid synthesis. Future research should elucidate the precise role of NMDA, MAPK and prostanoids in cerebral hyperperfusion. Moreover, research should focus on possible interventions and the effect of hypothermia on hyperperfusion. These findings should be taken into account simultaneously with brain imagining techniques, becoming a valuable asset in assessing the impact in neurodevelopmental outcome.