Effect of Early High-Dose Recombinant Human Erythropoietin on Behavior and Quality of Life in Children Aged 5 Years Born Very Preterm: Secondary Analysis of a Randomized Clinical Trial.

Importance: In light of the promising neuroprotective properties of recombinant human erythropoietin (RHEpo), the Swiss EPO Neuroprotection Trial was started to investigate its effect on neurodevelopment in very preterm infants. The results of the primary and secondary outcome analysis did not show any effect of RHEpo on cognitive performance, neuromotor outcomes, or somatic growth of the study participants at ages 2 or 5 years. Objective: To investigate whether early high-dose RHEpo improves behavioral outcomes and health-related quality of life (HRQoL) at age 5 years. Design, Setting, and Participants: This was a prespecified secondary analysis of the double-blind, placebo-controlled, multicenter Swiss EPO Neuroprotection randomized clinical trial, which was conducted at 5 level-III perinatal centers in Switzerland. Infants born between 26 weeks 0 days' and 31 weeks 6 days' gestation were recruited between 2005 and 2012 and followed-up until age 5 years (last follow-up in 2018). Data were analyzed from January 6 to December 31, 2021. Interventions: Infants were assigned to receive either RHEpo (3000 IU/kg) or placebo (saline, 0.9%) intravenously 3 times within the first 42 hours after birth. Main Outcomes and Measures: The prespecified parent-reported measures of behavioral outcomes and health-related quality of life (HRQoL) of their children at the age of 5 years were assessed by two standardized questionnaires: the Strengths and Difficulties Questionnaire (behavioral outcomes) and the KIDSCREEN-27 (HRQoL). Results: Among 448 randomized infants, 228 infants were assigned to the RHEpo group and 220 infants were assigned to the placebo group. Questionnaire data were available for 317 children (71%) at a mean (SD) age of 5.8 (0.4) years (mean [SD] gestational age at birth, 29.3 [1.6] weeks; mean [SD] birth weight 1220 [340] grams; 128 [40%] female infants). At the age 5 years follow-up, the mean (SD) total difficulties score in the RHEpo group (8.41 [5.60] points) was similar to that of the placebo group (7.76 [4.81]) (P = .37). There were no statistically significant differences between the groups in any other outcome measures. Conclusions and Relevance: This secondary analysis of a randomized clinical trial showed no evidence for an effect of early high-dose RHEpo administration on behavioral outcomes or HRQoL in children born very preterm at early school age. Trial Registration: ClinicalTrials.gov Identifier: NCT00413946.

Performance of the German version of the PARCA-R questionnaire as a developmental screening tool in two-year-old very preterm infants.

OBJECTIVE: To validate and test a German version of the revised Parent Report of Children's Abilities questionnaire (PARCA-R). METHODS: Multicentre cross-sectional study. Parents of infants born <32 gestational weeks, completed the PARCA-R within three weeks before the follow-up assessment of their child at age two years. Infants were assessed using the Mental Development Index (MDI) of the Bayley Scales of Infant Development 2nd edition (BSID-II). Pearson correlation between the Parent Report Composite (PRC) of the PARCA-R and MDI was tested. The optimal PRC cut-off for predicting moderate-to-severe mental delay, defined as MDI<70, was identified through the receiver operating characteristic (ROC) curve. RESULTS: PARCA-R and BSID-II data were collected from 154 consecutive infants [51% girls, mean (SD) gestational age 29.0 (2.0) weeks, birth weight 1174 (345) grams] at 23.2 (1.6) months of corrected age. The PRC score [70.5 (31.1)] correlated with the MDI [92.2 (17.3); R = 0.54; p < 0.0001]. The optimal PRC cut-off for identifying mental delay was 44 with 0.81 (0.54-0.96) sensitivity (95%-CI), 0.81 (0.74-0.87) specificity, area under the ROC curve of 0.840 (0.729-0.952). CONCLUSION: The German version of the PARCA-R had good validity with the BSID-II and PCR scores < 44 proved optimal discriminatory power for the identification of mental delay at two years of corrected age.

Early gut microbiota signature of aGvHD in children given allogeneic hematopoietic cell transplantation for hematological disorders.

BACKGROUND: The onset of acute Graft-versus-Host Disease (aGvHD) has been correlated with the gut microbiota (GM) composition, but experimental observations are still few, mainly involving cohorts of adult patients. In the current scenario where fecal microbiota transplantation has been used as a pioneer therapeutic approach to treat steroid-refractory aGvHD, there is an urgent need to expand existing observational studies of the GM dynamics in Hematopoietic Stem Cell Transplantation (HSCT). Aim of the present study is to explore the GM trajectory in 36 pediatric HSCT recipients in relation to aGvHD onset. METHODS: Thirty-six pediatric patients, from four transplantation centers, undergoing HSCT were enrolled in the study. Stools were collected at three time points: before HSCT, at time of engraftment and > 30 days following HSCT. Changes in the GM phylogenetic structure were studied by 16S rRNA gene Illumina sequencing and phylogenetic assignation. RESULTS: Children developing gut aGvHD had a dysbiotic GM layout before HSCT occurred. This putative aGvHD-predisposing ecosystem state was characterized by (i) reduced diversity, (ii) lower Blautia content, (iii) increase in Fusobacterium abundance. At time of engraftment, the GM structure underwent a deep rearrangement in all patients but, regardless of the occurrence of aGvHD and its treatment, it reacquired a eubiotic configuration from day 30. CONCLUSIONS: We found a specific GM signature before HSCT predictive of subsequent gut aGvHD occurrence. Our data may open the way to a GM-based stratification of the risk of developing aGvHD in children undergoing HSCT, potentially useful also to identify patients benefiting from prophylactic fecal transplantation.