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

Abstract

and for the PENUT Consortium 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.

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

“…Although several studies have compared the neurodevelopmental effects of restrictive and liberal transfusion guidelines and shown no difference in outcome, these studies have not compared the outcome of infants with no transfusions compared with those with 1 or more transfusion, or the effects of transfusion volume on outcomes. 28,[37][38][39] There is some suggestion that pRBC transfusions may be associated with worse neurodevelopmental outcomes. 28,40,41 Large studies have evaluated the association between different hematocrit thresholds and outcome but have not evaluated the impact of transfusion volume on neurodevelopment.…”

“…28,[37][38][39] There is some suggestion that pRBC transfusions may be associated with worse neurodevelopmental outcomes. 28,40,41 Large studies have evaluated the association between different hematocrit thresholds and outcome but have not evaluated the impact of transfusion volume on neurodevelopment. [37][38][39]42 Given potential negative effects of pRBC transfusions, including infection, inflammation, 43 transfusion-related necrotizing enterocolitis, 44 and potentially adverse developmental effects, it is ideal to implement strategies to minimize the need for transfusions, including delayed cord clamping, limiting phlebotomy, use of restrictive transfusion guidelines, and ESAs.…”

“…Second, linear associations were examined among all participants using GEE models adjusted for treatment group, gestational age at birth (grouped as 24/25 weeks or 26/27 weeks), recruitment site, potential confounding variables (Apgar score at 5 minutes, stage 2b or 3 necrotizing enterocolitis, intracranial hemorrhage [grade 3 or 4], severe sepsis [defined as culture-positive infection requiring blood pressure support and/or significant escalation in respiratory support], cumulative volume of packed red blood cell [pRBC] transfusion per kg to day 60), and maternal education. 28 We fitted similar GEE models but with the addition of interactions between cumulative enteral iron intake and treatment arm, to examine the potential Epo modification of the iron-outcome relationships of interest. The associations between BSID-III scores and cumulative iron intake were assessed within each treatment arm using GEE models adjusted for gestational age group, recruitment site, and similar potential confounding variables.…”

Prophylactic Erythropoietin for Neuroprotection in Very Preterm Infants: A Meta-Analysis Update

“…Interestingly, the post hoc analysis of the PENUT trial indicated that each transfusion of RBCs was associated with a decrease in mean cognitive score, motor score, and language score (BSID-III). Moreover, significant negative associations between BSID-III scores, transfusion volume, and donor exposure were observed in the placebo group, but not in the rhEPO group ( 14 ). Since an early start of rhEPO therapy significantly reduced the number of RBC transfusions, as shown in the updated Cochrane Review and in the recent PENUT trial ( 15 , 16 ), rhEPO may still reclaim its value in the patient blood management of very preterm infants.…”

Prematürede anemi ve transfüzyon politikaları

“…), İVK ve PVL riskini azalttığı; düzeltilmiş yaşı 18-22 aylık bebeklerde nörogelişimsel sonuçların daha iyi olduğu (Bayley II Mental Development Index skorlarının daha iyi olduğu), mortalite üzerine etkisiz ve evre ≥3 ROP riskinde anlamlı bir farklılığın olmadığı bildirilmekte, ancak kıstlı faydaları nedeniyle şu an için EPO kullanımı önerilmemektedir[43].Eritrosit transfüzyonunda, eritrosit süspansiyonunun depo süresinin transfüze edilen bebeklerdeki etkisinin incelendiği son meta analizde; kısa süreli (<7 gün) ya da uzun süreli olan eritrosit süspansiyonlarının yetişkin ve çocuklarda kısa dönemde (<30 gün) mortalite üzerine bir etkisinin olmadığı, yenidoğanlarla ilgili olarak ise yeterli verilerin bulunmadığı bildirilirken[20], ÇDDA'lı 377 bebeğin alındığı bir çalışmada taze (<7 gün) eritrosit süspansiyonu ile standart eritrosit süspansiyonu (2-42 gün) transfüze edilen bebeklerin 3 aylık izleminde; NEK, ROP, BPD, İVK, ölüm ve nozokomiyal enfeksiyon bakımından iki grup arasında anlamlı bir farklılığın olmadığı gösterilmiştir[21], ancak; yüksek volümlü transfüzyonlarda plazma potasyumunda artma, sitrat toksisitesine bağlı hipokalsemi gelişme riskleri bulunabilmektedir[6].Prematüre bebeklerde yaşamın ilk dönemlerinde her bir eritrosit transfüzyonun uzun dönemde; kognitif gecikme, dil ve motor fonksiyonlarda azalma ile ilişkili olduğu, transfüzyon sayısının azaltılması ile bu nörolojik hasarlanma riskinin azalabileceği, dolayısıyla restriktif eritrosit transfüzyon eşik değeri kullanımının uzun dönemde potansiyel olarak daha nöroprotektif gözüktüğü bildirilmektedir[61][62][63][64][65].…”