Three-Domain Serial Cranial Ultrasound Phenotypes and Outcomes in Very Preterm Infants with Severe Brain Injury: A Single-Center Cohort Study

Background/Objectives: Severe brain injury (SBI) in very preterm infants includes heterogeneous lesions with distinct timing, burden and outcomes. We used cranial ultrasound (CUS) to describe SBI entity, documented timing, three-domain burden, deaths following documented withdrawal, withholding or non-escalation of life-sustaining treatment for poor neurological prognosis (neuro-WWLST), and survivor outcomes. Methods: Retrospective single-center cohort (1991–2020) of 2841 very preterm infants (<32 weeks’ gestation and/or birth weight ≤ 1500 g) with complete CUS within 48 h after birth. CUS was summarized by four windows, three domains—parenchymal lesion, intraventricular hemorrhage (IVH) and ventriculomegaly—and three mutually exclusive entities: periventricular hemorrhagic infarction (PVHI), cystic periventricular leukomalacia (cPVL and grade 3 IVH without PVHI/cPVL (IVH3 entity). Cross-outcome analyses used common maximal-burden CUS. Results: SBI occurred in 286/2841 infants (10.1%) and neuro-WWLST death in 45/2841 infants (1.6%); 43/45 occurred within SBI, and 43/89 SBI deaths (48.3%) followed documented neuro-WWLST. Using common maximal-burden CUS, severe three-domain involvement was more frequent among neuro-WWLST deaths than survivors (37.2% vs. 8.6%). Among SBI survivors with follow-up, cerebral palsy (CP) occurred in 87/176 (49.4%) and clinically classified school-age cognitive sequelae in 50/155 (32.3%). Outcomes varied by entity, with mainly ambulatory unilateral CP after PVHI, more frequent non-ambulatory bilateral CP after cPVL, and a heterogeneous IVH3 profile. Severe three-domain involvement identified a small subgroup with higher outcome burden, but outcomes were not deterministic. Conclusions: A structured, descriptive CUS approach separating lesion entity, documented timing and multidomain burden may support transparent cohort-level description of SBI trajectories, documented neuro-WWLST deaths and survivor outcomes.