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

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.

Keywords: Epo; erythropoietin; extremely low gestational age neonate; extremely preterm neonate; iron; neonate; neurodevelopment; neurodevelopmental outcomes.

Conflict of interest statement

The authors declare no conflicts of interest.

Copyright © 2021 Elsevier Inc. All rights reserved.

Figures

Figure 1.

Iron Management (Ferritin or ZnPP/H may be used to assess iron status)

Figure 1; Online:. CONSORT diagram

The CONSORT diagram shows the number screened, eligible, randomized, and included in this post-hoc analysis from the parent PENUT Trial.

Figure 2:. Unadjusted linear trends in cumulative enteral iron supplementation at day 60 and BSID-III component scores at 2-years of age

Raw data on cumulative enteral iron supplementation at day 60 and BSID-III scores are shown, with unadjusted linear trends fitted by treatment group for cognitive component (panel A), motor component (panel B), and language component (panel C).

Figure 3:. Associations between cumulative iron intake at day 60 and BSID-III component scores at 2-years of age for all infants.

The associations between mean BSID-III component scores (cognitive, motor, and language) and cumulative enteral iron intake at day 60 in all infants were examined using GEE models clustering on same-birth siblings and adjusted for fixed effects of treatment group, gestational age group, recruitment site, Apgar score at 5 minutes, necrotizing enterocolitis (stage 2b or 3), severe intracranial hemorrhage, severe sepsis, and cumulative volume of pack red blood cell (pRBC) transfusion per kg at day 60. Cumulative IV iron at day 60 was adjusted in sensitivity analyses. [1] Results are reported as effect size of 50 mg/kg of cumulative enteral iron at day 60 on BSID-III scores [2] Positive values indicate that higher iron intake was associated with higher mean BSID-III score, adjusted for potential sibship correlations and confounding variables

Figure 4:. Associations between cumulative iron intake at day 60 and BSID-III component scores at 2-years of age by treatment arms.

The associations between mean BSID-III component scores (cognitive, motor, and language) and cumulative enteral iron intake at day 60 for infants in each treatment arm were examined using GEE models clustering on same-birth siblings and adjusted for fixed effects of gestational age group, recruitment site, Apgar score at 5 minutes, necrotizing enterocolitis (stage 2b or 3), severe intracranial hemorrhage, severe sepsis, and cumulative volume of pack red blood cell (pRBC) transfusion per kg at day 60. Cumulative IV iron at day 60 was adjusted in sensitivity analyses. [1] Results are reported as effect size of 50 mg/kg of cumulative enteral iron at day 60 on BSID-III scores [2] Positive values indicate that higher iron intake was associated with higher mean BSID-III score, adjusted for potential sibship correlations and confounding variables

Figure 5; online:. Effect sizes of cumulative pRBC transfusion volume at 60 days in statistical models examining the relationships between cumulative enteral iron intake at day 60 and BSID-III component scores.

The associations between mean BSID-III component scores (cognitive, motor, and language) and cumulative enteral iron intake at day 60 in all infants overall and by treatment group were examined using GEE models clustering on same-birth siblings and adjusted for potential confounding variables, which included cumulative volume of pack red blood cell (pRBC) transfusion per kg at day 60, as shown in Figures 3 and 4. This figure shows the effect size of cumulative pRBC transfusions in all of these statistical models, indicated as change in mean BSID-III scores corresponding to an increase of 15mL/kg in cumulative pRBC volume at day 60. [1] Results are reported as effect size of 15 mL/kg of cumulative transfusion volume at day 60 on BSID-III scores [2] Negative values indicate that higher cumulative transfusion volume was associated with lower mean BSID-III score, adjusted for potential sibship correlations, cumulative enteral iron, and confounding variables

Figure 6; online:. Unadjusted linear trends in cumulative enteral iron supplementation at 90 days and BSID-III component scores at 2-years of age

Raw data on cumulative enteral iron supplementation at day 90 and BSID-III scores are shown, with unadjusted linear trends fitted by treatment group for cognitive component (panel A), motor component (panel B), and language component (panel C).

Figure 7; online:. Associations between cumulative iron intake at day 90 and BSID-III component scores at 2-years of age for all infants and by treatment groups.

The associations between mean BSID-III component scores (cognitive, motor, and language) and cumulative enteral iron intake at day 60 in all infants were examined using GEE models clustering on same-birth siblings and adjusted for fixed effects of treatment group, gestational age group, recruitment site, Apgar score at 5 minutes, necrotizing enterocolitis (stage 2b or 3), severe intracranial hemorrhage, severe sepsis, and cumulative volume of pack red blood cell (pRBC) transfusion per kg at day 60. Cumulative IV iron at day 60 was adjusted in sensitivity analyses. Similar analyses were performed for infants in each treatment group. [1] Results are reported as effect size of 50 mg/kg of cumulative enteral iron at day 90 on BSID-III scores [2] Positive values indicate that higher iron intake was associated with higher mean BSID-III score, adjusted for potential sibship correlations and confounding variables

Figure 8; online:. Effect sizes of cumulative pRBC transfusion volume at 90 days in statistical models examining the relationships between cumulative enteral iron intake at day 90 and BSID-III component scores at 2-years of age

The associations between mean BSID-III component scores (cognitive, motor, and language) and cumulative enteral iron intake at day 90 in all infants overall and by treatment group were examined using GEE models clustering on same-birth siblings and adjusted for potential confounding variables, which included cumulative volume of pack red blood cell (pRBC) transfusion per kg at day 90, as shown in eFigure 3. This figure shows the effect size of cumulative pRBC transfusions in all of these statistical models, indicated as change in mean BSID-III scores corresponding to an increase of 15mL/kg in cumulative pRBC volume at day 90. [1] Results are reported as effect size of 15 mL/kg of cumulative transfusion volume at day 90 on BSID-III scores [2] Negative values indicate that higher cumulative transfusion volume was associated with lower mean BSID-III score, adjusted for potential sibship correlations, cumulative enteral iron, and confounding variables

Figure 9; online:. Associations between cumulative iron intake at day 60 and BSID-III component scores at 2-years of age for all infants, accounting for maternal education, stratified by treatment group

The associations between mean BSID-III component scores (cognitive, motor, and language) and cumulative enteral iron intake at day 60 in all infants were examined using GEE models clustering on same-birth siblings and adjusted for fixed effects of treatment group, gestational age group, recruitment site, Apgar score at 5 minutes, necrotizing enterocolitis (stage 2b or 3), severe intracranial hemorrhage, severe sepsis, cumulative volume of pack red blood cell (pRBC) transfusion per kg at day 60, and maternal education. Cumulative IV iron at day 60 was adjusted in sensitivity analyses. [1] Results are reported as effect size of 50 mg/kg of cumulative enteral iron at day 60 on BSID-III scores [2] Positive values indicate that higher iron intake was associated with higher mean BSID-III score, adjusted for potential sibship correlations and confounding variables, including maternal education

Figure 10; online:. Associations between cumulative iron intake at day 60 and BSID-III component scores at 2-years of age by treatment arm, accounting for maternal education

The associations between mean BSID-III component scores (cognitive, motor, and language) and cumulative enteral iron intake at day 60 for infants in each treatment arm were examined using GEE models clustering on same-birth siblings and adjusted for fixed effects of gestational age group, recruitment site, Apgar score at 5 minutes, necrotizing enterocolitis (stage 2b or 3), severe intracranial hemorrhage, severe sepsis, cumulative volume of pack red blood cell (pRBC) transfusion per kg at day 60, and maternal education. Cumulative IV iron at day 60 was adjusted in sensitivity analyses. [1] Results are reported as effect size of 50 mg/kg of cumulative enteral iron at day 60 on BSID-III scores [2] Positive values indicate that higher iron intake was associated with higher mean BSID-III score, adjusted for potential sibship correlations and confounding variables, including maternal education