Jeff Russ, MD, PhD
Premature infants are already at high risk of neurodevelopmental delay from prematurity alone, but additional injury from intraventricular hemorrhage (IVH) is all too common, occurring in up to a fifth of premature infants.1 Infants with IVH clearly cannot afford further brain injury, so providers have to remain vigilant for the delayed co-morbidity of post-hemorrhagic hydrocephalus (PHH), which can occur in a quarter of those with severe IVH.2 Red blood cell breakdown and the release of hemoglobin is proinflammatory and damages the choroid plexus and periventricular white matter. The products of cellular destruction are thought to clog cerebrospinal fluid (CSF) reabsorption and lead to hydrocephalus.1
Understanding the detailed pathophysiology of PHH could help neonatal providers determine which infants are most at risk and could also suggest future therapeutic strategies. A study by Mahaney et al. in the June 2020 issue of Stroke3 sets out to shed light on the relationship between the clearance of blood products from the CSF after IVH and the development of PHH.
Thirty-five premature neonates born before 30-weeks gestational age were included in the study: four with low grade IVH, six with high grade IVH, and nine with PHH. CSF collected for other clinical purposes was analyzed for markers of red blood cell breakdown (hemoglobin, bilirubin, and iron), proteins that interact with iron (ferritin, transferrin, and ceruloplasmin), and iron scavenging proteins (haptoglobin and hemopexin). Hemoglobin was the only marker uniquely and significantly elevated in neonates with PHH compared to all other groups. Ferritin was also elevated in neonates with PHH, but this was also seen in neonates with high grade IVH without PHH. Finally, the authors report a loose correlation between higher levels of hemoglobin, bilirubin, and ferritin and increasing ventricular size. These findings support the hypothesis that red blood cell breakdown and iron metabolism are linked to the development of PHH.
At first glance, it may not be surprising that PHH develops in neonates with more extensive IVH since a simple explanation is that the large hematoma obstructs the ventricular system. It may also be unsurprising that larger hemorrhages result in higher levels of red blood cell turnover and are therefore more likely to clog CSF reabsorption. However, the findings from Mahaney et al. are notable for two potential practical applications, one short-term and one longer-term.
First, the authors report a cutoff of 6.5 μg/mL for CSF hemoglobin and 555 ng/mL for CSF ferritin that can reliably distinguish neonates with PHH from those without. For neonates with IVH who receive a lumbar puncture as part of an infectious or metabolic workup, providers could include CSF hemoglobin and ferritin in their analysis. If values begin to approach the suggested cutoffs, it may help flag premature infants at risk of PHH. Longer-term, the exploration of specific components of heme and iron metabolism that increase with PHH provide clues about possible therapeutic targets that might improve outcomes for premature infants. Iron chelating agents have been demonstrated to reduce the risk of hydrocephalus in rodent models,4 and in combination with the data from Mahaney et al., neonatal neurology inches closer to the possibility that biochemical modulators of heme and iron metabolism could be employed clinically. Future trials will answer these questions, but Mahaney et al. have begun to unclog the research pipeline that will help improve neonatal brain health.
References:
1. Robinson S. Neonatal posthemorrhagic hydrocephalus from prematurity: pathophysiology and current treatment concepts. J Neurosurg Pediatr. 2012;9:242-258.
2. Christian EA, et al. Trends in hospitalization of preterm infants with intraventricular hemorrhage and hydrocephalus in the United States, 2000-2010. J Neurosurg Pediatr. 2016;17:260-269.
3. Mahaney KB, et al. Intraventricular hemorrhage clearance in human neonatal cerebrospinal fluid: associations with hydrocephalus. Stroke. 2020;51:1712-1719.
4. Gao C, et al. Role of red blood cell lysis and iron in hydrocephalus after intraventricular hemorrhage. J Cerebral Blood Flow & Metabolism. 2014;34:1070-1075.
