PROJECT SUMMARY/ABSTRACT Improved survival of very preterm infants has not translated into improved neurodevelopment at school age. One promising neuroprotective therapy is the use of erythropoiesis stimulating agents (ESAs) such as darbepoetin. Preclinical and preliminary clinical data suggest that darbepoetin treatment will lead to improved neurodevelopmental outcomes in high-risk preterm infants. The NHLBI-funded “Darbepoetin Trial to Improve Red Cell Mass and Neurodevelopment in Preterms” (Darbe Trial) is a multicenter masked, randomized trial to test the hypothesis that darbepoetin leads to improved neurodevelopment at 2 years in very preterm infants. In the current application, we propose the Darbepoetin Kindergarten Development Study (Darbe-KIDS) in which we will evaluate neurodevelopment in the same children at preschool and school age. The specific aims of Darbe-KIDS are to (1) test the impact of neonatal exposure to darbepoetin on neurodevelopment and behavior at 4.0-5.0 and 6.0-7.0 years corrected age; (2) test the impact of neonatal exposure to darbepoetin on longitudinal neurodevelopment and behavior from 2.0 to 7.0 years corrected age; and (3) evaluate mediating and moderating factors on the effects of darbepoetin on school functioning at 6.0-7.0 years corrected age. We hypothesize that preschool children treated with darbepoetin will have better cognitive, motor, and behavior outcomes at each time point and over time, as compared to those treated with placebo. Further, we hypothesize that executive function and cognition will be significant mediators and biological sex and family socioeconomic status will be significant moderators of the effects of darbepoetin on pre-academic skills and teacher-reported behavior and social skills. Darbe-KIDS builds on the collective expertise in follow-up of preterm infants among our core group of investigators and at the 16 clinical sites that enrolled children in the Darbe Trial and capitalizes on the existing infrastructure that supports both the Darbe Trial and other ongoing school-age studies funded by NHLBI. The study is led by a highly collaborative, interdisciplinary multi-PI team with extensive relevant experience studying the impacts of ESAs in preterm infants and a long history of successful collaborations in conducting high-quality developmental follow-up through school-age in large cohorts of high-risk infants. Darbe-KIDS will be the first comprehensive evaluation of developmental impacts over time and school functioning at school age in a large, multicenter cohort of school-age children treated with darbepoetin. In addition to providing critical data about the multidimensional effects of darbepoetin on outcomes through school age, Darbe-KIDS will yield novel and important data on school functioning in a large contemporary cohort of preterm infants treated in U.S. neonatal intensive care units. Results of this study will directly impact interpretation of the Darbe Trial and influence w...