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Randomized Controlled Trial
. 2020 Aug 11;324(6):560-570.
doi: 10.1001/jama.2020.10690.

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

Axel R Franz  1   2 , Corinna Engel  1 , Dirk Bassler  3 , Mario Rüdiger  4 , Ulrich H Thome  5 , Rolf F Maier  6 , Ingeborg Krägeloh-Mann  7 , Martina Kron  8 , Jochen Essers  9 , Christoph Bührer  10 , Georg Rellensmann  11 , Rainer Rossi  12 , Hans-Jörg Bittrich  13 , Claudia Roll  14 , Thomas Höhn  15 , Harald Ehrhardt  16 , Stefan Avenarius  17 , Hans Thorsten Körner  18 , Anja Stein  19 , Horst Buxmann  20 , Matthias Vochem  21 , Christian F Poets  2 ; ETTNO Investigators
Collaborators, Affiliations
Randomized Controlled Trial

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

Axel R Franz et al. JAMA. .

Erratum in

  • Nonauthor Collaborator Supplement.
    [No authors listed] [No authors listed] JAMA. 2022 Jul 12;328(2):217. doi: 10.1001/jama.2022.11106. JAMA. 2022. PMID: 35819445 Free PMC article. No abstract available.

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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Conflict of interest statement

Conflict of Interest Disclosures: Dr Kron reported receipt of personal fees from AbbVie Inc. Dr Poets reported receipt of speaker honoraria from Masimo Inc and Sentec AG. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flow of Participants in the Effects of Transfusion Thresholds on Neurocognitive Outcomes of Extremely Low-Birth-Weight Infants (ETTNO) Trial
RBCT indicates red blood cell transfusion. aMore than 1 reason was possible. bMore than 1 reason was possible. Because investigators’ decisions not to approach parents could have introduced selection bias (eg, by preventing the sickest infants to enter this study), the study population was compared with the cohort of the German Neonatal Network database and no indication of selection bias was found (eTable 3 in Supplement 2). c“Missed” indicates not approached despite being eligible; reason not known. dGestational age at birth <23 weeks was not a predefined exclusion criterion, but some centers opted not to include these infants. Ten infants with gestational age at birth <23 weeks are listed under various other exclusion criteria. eAccording to the investigator at the site, the parents provided consent, but during on-site monitoring (after discharge), no signed consent form was found, and investigators were unable to locate the family to renew the consent. fRandomization was stratified by center and birth weight stratum (400-749 g and 750-999 g). Stratification by 36 centers and variable block size (2-10) accounted for the difference in the number of enrolled infants between treatment groups.
Figure 2.
Figure 2.. Treatment Effect on Hematocrit and Number of Red Blood Cell Transfusions (RBCTs)
Weekly mean hematocrit values (limited to hematocrit values documented until 36 weeks of postmenstrual age and truncated when less than 20% of the population remained, ie, at 11 weeks of postnatal age). Week 1A refers to the days of the first week of postnatal age up to randomization and week 1B refers to the days of the first week of postnatal age after randomization. Hematocrit values were derived from clinically indicated complete blood cell counts (or, rarely, from centrifuged hematocrit capillaries), documented as observed. Hematocrit values of 36 patients at 4 centers were at least in part estimated from hemoglobin concentrations. For each week, a mean value of all documented hematocrit values was calculated, resulting in a weekly mean hematocrit for each infant who had ≥1 hematocrit measurement in that week. Boxes indicate interquartile ranges; bars inside the boxes, medians; circles inside boxes, means; whiskers, highest and lowest values within 1.5 times the interquartile range; and markers outside the boxes, outlying data. Weekly mean hematocrit values are significantly different between the treatment groups from week 1b through week 11. See eTable 6 in Supplement 2 for differences in means; see eFigure 3 in Supplement 2 for weekly mean hematocrit values in the per-protocol population.
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