Blood adenosine levels positively correlate to the white matter lesions in very low birth weight premature infants

Prematurity affects about 10% of pregnancies worldwide each year. In about 20% of very low birth weight (VLBW) premature infants, punctate white matter lesions (PWML) can be diagnosed at MRI at term equivalent age. PWML is accompanied by mild impairment in the development of white matter tracts, that can affect both long-term motor and cognitive performance. The principal factors involved in the pathophysiology of white matter lesions are intrinsic vulnerability, inflammation, and oxidative stress.

Aiming at early identification of preterm infants at risk for developing clinical complications, this retrospective study correlated blood adenosine levels to the development of complications or prematurity, especially those related to brain injury, in 56 VLBW infants admitted at the Neonatal Intensive Care Unit of Gaslini Pediatric Hospital. The blood adenosine content in the cohort, assayed by Mass Spectrometry on dried blood spots collected for newborn screening program for congenital disease, showed that Ado levels at 15 days of life positively correlated to the white matter lesions at MRI performed at term equivalent age (OR [95%CI] of 50.0 [3.6-688.3], p-value < 0.001), with a cut-off value of 1.58 μM. Adenosine was higher (2.50 μM vs. 0.96 μM) in those infants who developed brain white matter lesions. Neurodevelopmental outcome of the same infants, measured with Griffiths Mental Development Scales (GMDS) at 12 ± 2 months corrected age, was slight negatively correlated with adenosine blood levels at 15 days of life. This result appears confirmative of our previous finding of elevated Ado blood levels in VLBW, negatively correlated with birth weight.

It has been supposed that the brain sensory overstimulation caused by premature birth, together with multi drug exposure (affecting adenosine clearance) further compounded by the ambient higher oxygen levels may promote adenosine persistence in the circulation. In some VLBW predisposed premature infants a higher adenosine release from unmyelinated axons, typical of an immature brain, may occur. Immature adenosine clearance represents a further possible source of elevated blood adenosine. In turn, adenosine may induce the differentiation of Oligodendrocyte Progenitor Cells (OPC) to mature oligodendrocytes. This would result in a critical reduction in the absolute number of myelinizing oligodendrocytes at a later stage, potentially related to the impaired white matter maturation. These disturbances of neuronal maturation appear consistent with the typical "primary cerebral dysmaturation disorder" of prematurity. It has been supposed that such white matter vulnerability may be further accentuated from the interruption of fetal supply of ideal nutrients, in particular key lipids. Different complications of prematurity were also found consistent with Ado levels changes, but a major finding relates to PVWM. Notably, white matter lesions show a positive correlation also to retinopathy of prematurity (ROP), a condition in which inflammation and oxidative stress play a pivotal pathogenic role.

It remains to be investigated why some babies at 15 days have a significantly higher levels of adenosine compared to other not developing PVWM. Nonetheless, the present work suggested the reliability, confirmed by multivariate analysis, of blood adenosine levels at day 15 post birth as the major predictor of brain injury occurrence. A potential role of blood adenosine as a biomarker of complications of prematurity, especially brain injury, and of poor long-term outcome in VLBW infants, may pose the basis for the stratification of strategic early postnatal neuroprotective interventions.