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Original Investigation
August 11, 2020

Effects of Liberal vs Restrictive Transfusion Thresholds on Survival and Neurocognitive Outcomes in Extremely Low-Birth-Weight Infants: The ETTNO Randomized Clinical Trial

Author Affiliations
  • 1Center for Pediatric Clinical Studies, University Children’s Hospital Tübingen, Tübingen, Germany
  • 2Neonatology, University Children’s Hospital Tübingen, Tübingen, Germany
  • 3University Hospital Zurich, Department of Neonatology, University of Zurich, Zurich, Switzerland
  • 4Clinic for Pediatrics, Department for Neonatology and Pediatric Intensive Care Medicine, Medical Faculty, TU Dresden, Dresden, Germany
  • 5Children’s Hospital, Division of Neonatology, Department of Women and Children’s Health, University of Leipzig, Leipzig, Germany
  • 6Children’s Hospital, University Hospital, Philipps University Marburg, Marburg, Germany
  • 7Department of Paediatric Neurology and Developmental Medicine, University Children’s Hospital Tübingen, Tübingen, Germany
  • 8Institute for Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany
  • 9University Hospital Ulm, Ulm, Germany
  • 10Charité Universitätsmedizin Berlin, Berlin, Germany
  • 11Pediatrics, University Hospital Münster, Münster, Germany
  • 12Vivantes Klinikum Neukölln, Berlin, Germany
  • 13Helios Klinikum Erfurt, Erfurt, Germany
  • 14Vestische Kinder-und Jugendklinik Datteln, Universität Witten/Herdecke, Datteln, Germany
  • 15Neonatology and Pediatric Intensive Care, University Hospital Düsseldorf, Düsseldorf, Germany
  • 16Department of General Pediatrics and Neonatology, Justus-Liebig-University Giessen, Giessen, Germany
  • 17Pediatrics, University Hospital Magdeburg, Magdeburg, Germany
  • 18Neonatology, Klinikum Links der Weser, Bremen, Germany
  • 19Department of Paediatrics I, University Duisburg-Essen, Essen, Germany
  • 20University Hospital Frankfurt, Frankfurt, Germany
  • 21Olgahospital, Klinikum Stuttgart, Stuttgart, Germany
JAMA. 2020;324(6):560-570. doi:10.1001/jama.2020.10690
Key Points

Question  Do liberal vs restrictive transfusion strategies in extremely low-birth-weight infants improve survival and neurodevelopmental outcome at 24 months of corrected age?

Findings  In this randomized clinical trial that included 1013 infants with birth weights less than 1000 g, a strategy of liberal blood transfusions compared with restrictive blood transfusions resulted in a composite outcome of death or disability at 24 months of corrected age in 44.4% vs 42.9%, respectively, a difference that was not statistically significant.

Meaning  Among extremely low-birth-weight infants, a liberal blood transfusion strategy did not reduce the likelihood of death or disability at 24 months compared with a restrictive strategy.

Abstract

Importance  Red blood cell transfusions are commonly administered to infants weighing less than 1000 g at birth. Evidence-based transfusion thresholds have not been established. Previous studies have suggested higher rates of cognitive impairment with restrictive transfusion thresholds.

Objective  To compare the effect of liberal vs restrictive red blood cell transfusion strategies on death or disability.

Design, Setting, and Participants  Randomized clinical trial conducted in 36 level III/IV neonatal intensive care units in Europe among 1013 infants with birth weights of 400 g to 999 g at less than 72 hours after birth; enrollment took place between July 14, 2011, and November 14, 2014, and follow-up was completed by January 15, 2018.

Interventions  Infants were randomly assigned to liberal (n = 492) or restrictive (n = 521) red blood cell transfusion thresholds based on infants’ postnatal age and current health state.

Main Outcome and Measures  The primary outcome, measured at 24 months of corrected age, was death or disability, defined as any of cognitive deficit, cerebral palsy, or severe visual or hearing impairment. Secondary outcome measures included individual components of the primary outcome, complications of prematurity, and growth.

Results  Among 1013 patients randomized (median gestational age at birth, 26.3 [interquartile range {IQR}, 24.9-27.6] weeks; 509 [50.2%] females), 928 (91.6%) completed the trial. Among infants in the liberal vs restrictive transfusion thresholds groups, respectively, incidence of any transfusion was 400/492 (81.3%) vs 315/521 (60.5%); median volume transfused was 40 mL (IQR, 16-73 mL) vs 19 mL (IQR, 0-46 mL); and weekly mean hematocrit was 3 percentage points higher with liberal thresholds. Among infants in the liberal vs restrictive thresholds groups, the primary outcome occurred in 200/450 (44.4%) vs 205/478 (42.9%), respectively, for a difference of 1.6% (95% CI, −4.8% to 7.9%; P = .72). Death by 24 months occurred in 38/460 (8.3%) vs 44/491 (9.0%), for a difference of −0.7% (95% CI, −4.3% to 2.9%; P = .70), cognitive deficit was observed in 154/410 (37.6%) vs 148/430 (34.4%), for a difference of 3.2% (95% CI, −3.3% to 9.6%; P = .47), and cerebral palsy occurred in 18/419 (4.3%) vs 25/443 (5.6%), for a difference of −1.3% (95% CI, −4.2% to 1.5%; P = .37), in the liberal vs the restrictive thresholds groups, respectively. In the liberal vs restrictive thresholds groups, necrotizing enterocolitis requiring surgical intervention occurred in 20/492 (4.1%) vs 28/518 (5.4%); bronchopulmonary dysplasia occurred in 130/458 (28.4%) vs 126/485 (26.0%); and treatment for retinopathy of prematurity was required in 41/472 (8.7%) vs 38/492 (7.7%). Growth at follow-up was also not significantly different between groups.

Conclusions and Relevance  Among infants with birth weights of less than 1000 g, a strategy of liberal blood transfusions compared with restrictive transfusions did not reduce the likelihood of death or disability at 24 months of corrected age.

Trial Registration  ClinicalTrials.gov Identifier: NCT01393496

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