Authors’ Reply to Chevle et al.: Comment on “Erythropoietin Improves Poor Outcomes in Preterm Infants with Intraventricular Hemorrhage”

Abstract

We thank Dr Chevle and colleagues for their interest in our study [1, 2].Very preterm infants have a high risk of complications such as intraventricular hemorrhage (IVH), periventricular white matter injury, and necrotizing enterocolitis, which may lead to death; those preterm infants that survive often have neurodevelopmental impairments. IVH is one of the most common gestational age-related short-term complications, and currently there are no effective therapeutic interventions. We previously showed that low-dose recombinant human erythropoietin (rhEPO) improves neurological outcomes in very preterm infants and tends to reduce mortality [3]. Thus, the main purpose of this study was to investigate whether or not low-dose rhEPO improve overall outcomes—including death and neurodevelopmental impairments—in very preterm infants with IVH [2]. We found that even though low-dose rhEPO improved overall outcomes of IVH in very preterm infants, the reduction in neurological disability did not reach statistical significance. Analyzing the results, we observed a lower incidence of neurological disability (16.9% in the placebo group and 8.8% in the rhEPO group) [2] compared with what was assumed (47%) based on a previously publication [4]. This might be because the percentage of extremely preterm infants in the current study was lower (< 15% of the study population) than the reference data, which included only extremely low birth weight infants [4], and because there have been more widely applied advanced perinatal support strategies in the neonatal care unit for very preterm infants in the hospital. In addition, the number of infants lost to follow up in this study [2] was also higher than in our previous study [3] (13.2% vs 10.1%). All of these factors together may indeed have caused a lower power than what was estimated when designing the study, and this might have affected the results. However, we believe that the current study still adds a great deal of value to the existing literature, and is also useful to serve as a reference for the incidence of neurological disability or poor outcomes at 18 months of corrected age in very preterm infants with IVH, which, to our knowledge, is lacking sufficient data for helping with sample size estimation for outcomes at this age. Loss to follow up is always among the first factors to be considered when designing a clinical study. We carefully analyzed the discharge records of the lost to followup infants, and we did not find any tendency for potential favorable or unfavorable outcomes. Instead, most of the lost to follow-up infants were from small towns or regions that are far away from the hospital, thus it was difficult to apply additional measures based on the conditions in those regions. It is unlikely, therefore, that the lost to follow-up infants were solely those with unfavorable outcomes in our study. Long-term follow up is also one of the most challenging issues for clinical studies in infants, and we are continuously investigating the addition of more measures to enhance this part of our studies. In this study, we focused on the long-term effects of low-dose rhEPO on the outcomes of IVH in very preterm infants at 18 months of corrected age. Blood transfusion and post-hemorrhagic ventricular dilation usually occurred < 3 This reply refers to the comment available online at https:// doi. org/ 10. 1007/ s4026302100857-2.