Transfusions and neurodevelopmental outcomes in extremely low gestation neonates enrolled in the PENUT Trial: a randomized clinical trial

Abstract

Background: Outcomes of extremely low gestational age neonates (ELGANs) may be adversely impacted by packed red blood cell (pRBC) transfusions. We investigated the impact of transfusions on neurodevelopmental outcome in the Preterm Erythropoietin (Epo) Neuroprotection (PENUT) Trial population.

Methods: This is a post hoc analysis of 936 infants 24-0/6 to 27-6/7 weeks' gestation enrolled in the PENUT Trial. Epo 1000 U/kg or placebo was given every 48 h × 6 doses, followed by 400 U/kg or sham injections 3 times a week through 32 weeks postmenstrual age. Six hundred and twenty-eight (315 placebo, 313 Epo) survived and were assessed at 2 years of age. We evaluated associations between BSID-III scores and the number and volume of pRBC transfusions.

Results: Each transfusion was associated with a decrease in mean cognitive score of 0.96 (95% CI of [-1.34, -0.57]), a decrease in mean motor score of 1.51 (-1.91, -1.12), and a decrease in mean language score of 1.10 (-1.54, -0.66). Significant negative associations between BSID-III score and transfusion volume and donor exposure were observed in the placebo group but not in the Epo group.

Conclusions: Transfusions in ELGANs were associated with worse outcomes. We speculate that strategies to minimize the need for transfusions may improve outcomes.

Impact: Transfusion number, volume, and donor exposure in the neonatal period are associated with worse neurodevelopmental (ND) outcome at 2 years of age, as assessed by the Bayley Infant Scales of Development, Third Edition (BSID-III). The impact of neonatal packed red blood cell transfusions on the neurodevelopmental outcome of preterm infants is unknown. We speculate that strategies to minimize the need for transfusions may improve neurodevelopmental outcomes.

Trial registration: ClinicalTrials.gov NCT03169881.

Fig. 1. CONSORT diagram.

This figure shows the infants screened, enrolled, randomized to Epo or placebo, and transfusion records analyzed.

Fig. 2. Primary analysis of BSID-III component scores and pRBC transfusion exposures.

The overall associations between mean BSID-III component scores (cognitive, motor, and language) and pRBC transfusion exposures (number of transfusions, cumulative volume of transfusion, and donor exposure) were examined using GEE models clustering on same-birth siblings, adjusted for fixed effects of treatment group, gestational age group, recruitment site, and other potential confounders at baseline. These associations were also evaluated for each treatment group using similar GEE models. The forest plot shows the estimated effect sizes of transfusion exposures on mean BSID-III scores and corresponding 95% CIs.

Fig. 3. BSID-III component scores and any pRBC transfusion.

The distributions of BSID-III a cognitive scores, b motor scores, and c language scores were summarized for those who were transfusion-free and who had ≥1 pRBC transfusion, overall and by treatment group. The overall associations among all participants were examined using GEE models clustering on same-birth siblings, adjusted for fixed effects of treatment group, gestational age group, recruitment site, and other potential confounding variables at baseline. These associations were also evaluated for each treatment group using similar GEE models.

Fig. 4. Secondary ND outcomes and pRBC transfusion exposures.

The overall associations between secondary ND outcomes and pRBC transfusion exposures were examined using GEE loglinear models clustering on same-birth siblings, adjusted for fixed effects of treatment group, gestational age group, and other potential confounding covariates at baseline. These associations were also evaluated for each treatment group using similar GEE models. The forest plot shows the estimated effect sizes of transfusion exposures on the RR of ND outcomes and corresponding 95% CIs. RRs >1.0 indicate that exposure to pRBC transfusions is associated with higher risk of worse ND outcomes.