Tract-based spatial statistics to assess the neuroprotective effect of early erythropoietin on white matter development in preterm infants

Abstract

Despite improved survival, many preterm infants undergo subsequent neurodevelopmental impairment. To date, no neuroprotective therapies have been implemented into clinical practice. Erythropoietin, a haematopoietic cytokine used for treatment of anaemia of prematurity, has been shown to have neuroprotective and neuroregenerative effects on the brain in many experimental studies. The aim of the study was to assess the effect of recombinant human erythropoietin on the microstructural development of the cerebral white matter using tract-based spatial statistics performed at term equivalent age. A randomized, double-blind placebo-controlled, prospective multicentre study applying recombinant human erythropoietin in the first 42 h after preterm birth entitled 'Does erythropoietin improve outcome in preterm infant' was conducted in Switzerland (NCT00413946). Preterm infants were given recombinant human erythropoietin (3000 IU) or an equivalent volume of placebo (NaCl 0.9%) intravenously before 3 h of age after birth, at 12-18 h and at 36-42 h after birth. High resolution diffusion tensor imaging was obtained at 3 T in 58 preterm infants with mean (standard deviation) gestational age at birth 29.75 (1.44) weeks, and at scanning at 41.1 (2.09) weeks. Imaging was performed at a single centre. Voxel-wise statistical analysis of the fractional anisotropy data was carried out using tract-based spatial statistics to test for differences in fractional anisotropy between infants treated with recombinant human erythropoietin and placebo using a general linear model, covarying for the gestational age at birth and the corrected gestational age at the time of the scan. Preterm infants treated with recombinant human erythropoietin demonstrated increased fractional anisotropy in the genu and splenium of the corpus callosum, the anterior and posterior limbs of the internal capsule, and the corticospinal tract bilaterally. Mean fractional anisotropy was significantly higher in preterm infants treated with recombinant human erythropoietin than in those treated with placebo (P < 0.001). We conclude that early recombinant human erythropoietin administration improves white matter development in preterm infants assessed by diffusion tensor imaging and tract-based spatial statistics.

Recombinant human erythropoietin improves neurological outcomes in very preterm infants

“…This high‐dose rhEPO in rodents was equivalent to that in preterm infants given at a high dose of 1,000 to 2,500U/kg 20. Based on those results from neonatal rodent brain injury models, clinical studies showed that high‐dose rhEPO (2,500–3,000U/kg) administered after birth was well tolerated in preterm and term infants14, 20, 33, 37, 42 and conferred neuroprotection 16, 36. In a previous study using low‐dose rhEPO to prevent anemia in preterm infants, it was observed that preterm infants with rhEPO treatment also had significant neurodevelopmental improvement 38.…”

“…Recent experimental34, 35 and clinical17, 36, 37, 38 studies indicate that rhEPO is a promising candidate for very preterm infants with brain injury and that it improves neurodevelopment and reduces the risk of neurodevelopmental disability. However, the safe dose range, timing, and duration of rhEPO administration still require careful exploration and consideration.…”

Erythropoietin for the Repair of Cerebral Injury in Very Preterm Infants (EpoRepair)

“…Previous studies in preterm and term infants found 1,000 and 2,500 IU rEPO/kg BW per dose given intravenously well tolerated and sufficient to produce plasma concentrations that are neuroprotective in animals [33,34]. In the recently completed first large high-dose rEPO trial in very preterm infants, 3,000 IU rEPO/kg BW per dose given intravenously were safe [28] and resulted in promising brain MRI findings [29,30]. In terms of a pragmatic approach, and also with the aim to add further data with regard to the optimal neuroprotective dosing in very preterm infants, we opted for an intermediate dosage, namely for 2,000 IU/kg BW.…”

“…A qualitative and quantitative MRI was performed in a subset of patients at TEA. The MRI findings show that early high-dose rEPO administration resulted in less WM and gray matter injury and in improved WM microstructure [29,30]. Neurodevelopmental follow-up of the study patients will demonstrate whether these promising MRI findings will translate into improved long-term outcomes [31].…”

Preschool Assessment of Preterm Infants Treated With Darbepoetin and Erythropoietin

“…Leuchter et al 17 reported decreased gray and white matter injury in 77 of the erythropoietin-treated infants compared with 88 placebo-treated infants, and O'Gorman et al 18 reported improved white matter development as assessed by diffusion tensor imaging and tract-based spatial statistics in 24 of the erythropoietin-treated infants compared with 34 placebotreated infants. A US multicenter trial of high-dose erythropoietin for neuroprotection in 960 extremely low gestational age infants (PENUT [Preterm Epo Neuroprotection Trial]; NCT01534481) is ongoing, and neurodevelopmental outcomes are expected in ∼3 years.…”