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

Abstract

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.

Figure.. Participant Recruitment Flowchart

KIDSCREEN-27 indicates the parent version of the KIDSCREEN-27 (KS-27) questionnaire used to evaluate health-related quality of life; SDQ, the parent version of the Strengths and Difficulties Questionnaire used to evaluate behavioral outcomes. ^aDecision to provide primary nonintervention and palliative care after delivery was made antenatally with the agreement of the parents if several known prognostic factors were so unfavorable that the initiation of intensive care measures appeared to be inappropriate. ^bInfants received lower than allocated dose after randomization, which occurred before 3 hours of life, exclusion criteria (5 infants), or nonadherence to inclusion criteria (attributable to errors in reporting of gestational age for 2 infants) were discovered for some infants; thus, they were excluded after randomization. ^cInfants received supplemental recombinant human erythropoietin (RHEpo) to treat anemia of prematurity during the later neonatal course. ^dExcluded after administration of the assigned treatment because of a uniparental disomy 16 and a dysmorphic syndrome that became evident after the third day of life (genetic investigations were still ongoing at the time of manuscript submission).