Epigenetic modifications of VEGF, cerebral hypoxia and impaired cerebrovascular autoregulation as early indicators for preterm brain injury

Neurodevelopmental impairments after preterm birth remain prevalent. Preterm brain injury, such as intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL), occurs due to immature vascularization and impaired cerebral blood flow. We explored epigenetic changes in the vascular endothelial growth factor A ( VEGFA) and cerebrovascular autoregulation as biomarkers for preterm brain injury. Preterm neonates <30 weeks gestational age and/or <1000 grams were prospectively enrolled in a single-center observational cohort study. We compared cerebral hemodynamics and cerebrovascular autoregulation during the first three postnatal days and VEGFA methylation from buccal samples during the first two weeks between neonates without brain injury and those with IVH, PVL or with IVH and/or PVL. Of 73 neonates with a mean±SD gestational age and birth weight of 27.7±1.6 weeks and 1017±235 grams, 33 (45.2%) had IVH and/or PVL. Upon multivariable regression, IVH was associated with sedation, cerebral hypoxia and impaired cerebrovascular autoregulation on day 3. Neonates with PVL had more methylated VEGFA in both weeks (median week1 3.12% vs. 2.50%, p=0.022). Upon multivariable regression, PVL was associated with lower Apgar scores and VEGFA hypermethylation in week 2. Neonates with IVH and/or PVL had lower cerebral tissue oxygenation (p day1 =0.005, p day3 =0.001) and more impaired cerebrovascular autoregulation on day 1 (p<0.001) than those without cerebral injury. Our findings indicate associations between both hemodynamic and epigenetic biomarkers and preterm brain injury. IVH and PVL showed associations with impaired cerebrovascular autoregulation, while IVH was associated with cerebral hypoxia and PVL with epigenetic downregulation of VEGFA. Hemodynamic changes appeared early postnatally, underscoring their clinical relevance.