From hemorrhage to hydrocephalus: cerebrospinal fluid biomarkers and molecular pathways associated with posthemorrhagic ventricular dilatation in preterm infants — a systematic review and meta-analysis

Abstract

Posthemorrhagic ventricular dilatation (PHVD) and posthemorrhagic hydrocephalus (PHH) are major complications of germinal matrix–intraventricular hemorrhage (GMH-IVH) in preterm infants. Although serial cranial ultrasonography remains central to clinical monitoring, the molecular mechanisms underlying progression from intraventricular hemorrhage to persistent ventricular dilatation and hydrocephalus are incompletely understood. Reliable cerebrospinal fluid (CSF) biomarkers that could identify infants at risk of progressive PHVD or permanent CSF diversion are currently lacking. This systematic review and meta-analysis aims to comprehensively evaluate molecular and biochemical CSF biomarkers investigated in preterm infants with IVH, PHVD, or PHH. The primary objectives are to identify biomarkers associated with PHVD progression and the requirement for permanent CSF diversion, distinguish prognostic evidence from disease-state associations, and characterize the molecular pathways implicated in posthemorrhagic hydrocephalus. The review examines inflammatory mediators, extracellular matrix remodeling factors, iron and hemoglobin degradation products, markers of neuronal and glial injury, angiogenic factors, and other CSF-associated molecular pathways. A systematic literature search was conducted in PubMed, Embase via Ovid, and Web of Science Core Collection, with the final search performed on 14 October 2026. Eligible studies include original human research published from January 1995 onward involving preterm infants with IVH, PHVD, or PHH and reporting molecular or biochemical CSF biomarkers. Two reviewers independently assessed study eligibility, extracted relevant data, and evaluated methodological quality, resolving disagreements through consensus. Evidence is synthesized narratively according to biomarker pathways, study design, and clinical relevance. Where sufficiently comparable quantitative data are available, meta-analyses are performed, accounting for overlapping patient cohorts to avoid double-counting. The review is expected to clarify which CSF biomarkers have demonstrated associations with PHVD progression or CSF diversion, identify limitations in the existing evidence, and highlight promising molecular targets for future prospective studies. Ultimately, this work aims to inform biomarker-driven risk stratification and improve understanding of the pathophysiology of PHVD in preterm infants. Registration status: This registration is retrospective. Literature searching, eligibility screening, and substantial portions of data extraction and synthesis were completed before registration. The record is intended to provide transparent, time-stamped documentation of the review methodology and does not constitute prospective preregistration.