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Endothelial progenitor cells in preterm infants with retinopathy of prematurity

To the Editor, The field of endothelial progenitor cells (EPCs) continues to evolve as this cell population is believed to be involved in vasculogenesis, angiogenesis, and in tissue regeneration by homing to sites of tissue injury to restore vascular integrity and ensure normal endothelial function. The putative role of EPCs regarding pregnancy and prematurity‐related complications, such as pre‐eclampsia, fetal growth restriction, gestational diabetes mellitus, bronchopulmonary dysplasia, and retinopathy of prematurity (ROP) has been addressed in numerous studies. However, the results are inconclusive suggesting that further research is needed to unravel the mechanisms involved in alterations of EPCs in preterm birth and to identify potential new treatment modalities to restore their function. We read with interest the recent report by Babaei et al, which suggests that increased circulating levels of endothelial progenitor cells (cEPCs) may be associated with higher risk of ROP in preterm infants. In this study, the authors evaluated the concentration of cEPCs and thoroughly analyzed the biological features of these cells, including secretion of angiogenic factors, proliferation, migration, and tubulogenesis activities. However, some missing information from the paper needs clarification; otherwise interpretation may be misleading. First, the age of the infants when the peripheral blood samples were taken is not described in the paper. In current literature no consensus has yet been reached about the effect of circulating levels of EPCs in ROP. Some studies have shown that circulating EPCs levels in preterm infants (with or without ROP) at birth are equal or higher than in full‐term. Then, they decrease gradually over the first six weeks of postnatal life until they reach similar numbers to those observed in term infants. Similarly, it has been observed that preterm infants with ROP have higher levels of EPCs at birth compared with preterm infants without ROP. However, at the sixth week after birth the count of EPCs in preterm infants with ROP has been found to be lower than in preterm infants without the disease. It is believed that EPCs are bone‐marrow derived cells that are mobilized into the peripheral blood in response to ischemia or tissue injury. The circulating levels of these cells might correlate with the development of ROP in preterm infants. However, the level of EPCs in the peripheral blood is associated with the age of the subject, so no interpretation can be attempted if this factor is not taken into account. Another issue to highlight is that the three groups compared were not age‐matched. Machalinska et al. demonstrated that at 10 weeks after birth cEPC levels in the peripheral blood were higher in preterm compared with full‐term infants, as well as in preterm infants who developed ROP (≥ stage 3) compared with those who did not, a difference which remained statistically significant after adjustment for gestational age. In another study by the same authors it has been reported that EPC count in the peripheral blood of preterm infants with treatment‐ requiring ROP decreased after successful laser photocoagulation and regression of the pathological vessels. However, EPC count was measured in the same infants before and after the treatment without a control group, so it is uncertain if the decrease was the result of the treatment or a consequence of the evolution in time. To clarify if the levels of EPCs in the compared groups are linked to their state of prematurity, their state of retinopathy or their post‐menstrual age it is necessary to remove the confounding caused by age. Finally, there are a few more issues we would like to discuss. In the text it is stated that there is a statistically significant difference in some neonatal factors between the three groups. However, in Table 1 the P value (>0.05) does not appear to be significant and in page 4, a statistical significance for CD34 + among study groups is accompanied with a P value of less than 0.5. If the results of Babaei et al are to be applicable in future research, it is important to associate them with the age of the study population at the time of the blood sample collection so as to attempt associations and draw sensible conclusions.