Enteral Iron Supplementation in Infants Born Extremely Preterm and its Positive Correlation with Neurodevelopment; Post Hoc Analysis of the Preterm Erythropoietin Neuroprotection Trial Randomized Controlled Trial

PENUT Consortium

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8 Scopus citations

Abstract

Objectives: To test whether an increased iron dose is associated with improved neurodevelopment as assessed by the Bayley Scales of Infant Development, third edition (BSID-III) among infants enrolled in the Preterm Erythropoietin (Epo) Neuroprotection Trial (PENUT). Study design: This is a post hoc analysis of a randomized trial that enrolled infants born at 24-28 completed weeks of gestation. All infants in PENUT who were assessed with BSID-III at 2 years were included in this study. The associations between enteral iron dose at 60 and 90 days and BSID-III component scores were evaluated using generalized estimating equations models adjusted for potential confounders. Results: In total, 692 infants were analyzed (355 placebo, 337 Epo). Enteral iron supplementation ranged from 0 to 14.7 mg/kg/d (IQR 2.1-5.8 mg/kg/d) at day 60, with a mean of 3.6 mg/kg/d in infants treated with placebo and 4.8 mg/kg/d in infants treated with Epo. A significant positive association was seen between BSID-III cognitive scores and iron dose at 60 days, with an effect size of 0.77 BSID points per 50 mg/kg increase in cumulative iron dose (P =.03). Greater iron doses were associated with greater motor and language scores but did not reach statistical significance. Results at 90 days were not significant. The effect size in the infants treated with Epo compared with placebo was consistently greater. Conclusions: A positive association was seen between iron dose at 60 days and cognitive outcomes. Our results suggest that increased iron supplementation in infants born preterm, at the doses administered in the PENUT Trial, may have positive neurodevelopmental effects, particularly in infants treated with Epo. Trial registration: Clinicaltrials.gov: NCT01378273.

Original languageEnglish (US)
Pages (from-to)102-109.e8
JournalJournal of Pediatrics
Volume238
Early online dateJul 27 2021
DOIs
StatePublished - Nov 2021

Bibliographical note

Funding Information:
The PENUT Trial was funded by the National Institute of Neurological Disorders and Stroke (NINDS): U01NS077955, U01NS077953. The National Institutes of Health (NINDS) did not contribute significantly to the design and conduct of this post hoc analysis; collection, management, analysis and interpretation of the data; preparation, review and approval of the manuscript; or the decision to submit this post hoc analysis for publication. The authors declare no conflicts of interest.We thank Roberta Ballard, MD, for her unflagging support and advice throughout this trial; Karl Kuban and Mike O'Shea for leading the standardized neurologic examination training; and Jean Lowe for leading the standardized BSID-III certification. We thank the research coordinators from all 19 sites and 30 hospitals who made this study possible, and Mark A. Konodi (University of Washington) and Christopher Nefcy (University of Washington) and the Data Coordinating Center for keeping the PENUT Portal running. We thank the PENUT Medical Monitor John A. Widness, MD (University of Iowa) for his meticulous work during the years of PENUT enrollment, and members of the PENUT DSMB.

Funding Information:
The PENUT Trial was funded by the National Institute of Neurological Disorders and Stroke (NINDS): U01NS077955 , U01NS077953 . The National Institutes of Health (NINDS) did not contribute significantly to the design and conduct of this post hoc analysis; collection, management, analysis and interpretation of the data; preparation, review and approval of the manuscript; or the decision to submit this post hoc analysis for publication. The authors declare no conflicts of interest.

Publisher Copyright:
© 2021 Elsevier Inc.

Keywords

  • Epo
  • erythropoietin
  • extremely low gestational age neonate
  • extremely preterm neonate
  • iron
  • neonate
  • neurodevelopment
  • neurodevelopmental outcomes

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