Higher or Lower Hemoglobin Transfusion Thresholds for Preterm Infants

Abstract

Background: Limited data suggest that higher hemoglobin thresholds for red-cell transfusions may reduce the risk of cognitive delay among extremely-low-birth-weight infants with anemia.

Methods: We performed an open, multicenter trial in which infants with a birth weight of 1000 g or less and a gestational age between 22 weeks 0 days and 28 weeks 6 days were randomly assigned within 48 hours after delivery to receive red-cell transfusions at higher or lower hemoglobin thresholds until 36 weeks of postmenstrual age or discharge, whichever occurred first. The primary outcome was a composite of death or neurodevelopmental impairment (cognitive delay, cerebral palsy, or hearing or vision loss) at 22 to 26 months of age, corrected for prematurity.

Results: A total of 1824 infants (mean birth weight, 756 g; mean gestational age, 25.9 weeks) underwent randomization. There was a between-group difference of 1.9 g per deciliter (19 g per liter) in the pretransfusion mean hemoglobin levels throughout the treatment period. Primary outcome data were available for 1692 infants (92.8%). Of 845 infants in the higher-threshold group, 423 (50.1%) died or survived with neurodevelopmental impairment, as compared with 422 of 847 infants (49.8%) in the lower-threshold group (relative risk adjusted for birth-weight stratum and center, 1.00; 95% confidence interval [CI], 0.92 to 1.10; P = 0.93). At 2 years, the higher- and lower-threshold groups had similar incidences of death (16.2% and 15.0%, respectively) and neurodevelopmental impairment (39.6% and 40.3%, respectively). At discharge from the hospital, the incidences of survival without severe complications were 28.5% and 30.9%, respectively. Serious adverse events occurred in 22.7% and 21.7%, respectively.

Conclusions: In extremely-low-birth-weight infants, a higher hemoglobin threshold for red-cell transfusion did not improve survival without neurodevelopmental impairment at 22 to 26 months of age, corrected for prematurity. (Funded by the National Heart, Lung, and Blood Institute and others; TOP ClinicalTrials.gov number, NCT01702805.).

Figure 1 (facing page).. Screening, Randomization, Intervention, and Follow-up.

Infants were screened for eligibility only if they met the inclusion criteria of a birth weight of 1000 g or less, a gestational age between 22 weeks 0 days and 28 weeks 6 days, admission to the center neonatal intensive care unit within 48 hours after birth, and the ability to undergo randomization within 48 hours after birth. The assigned intervention was to extend until 36 weeks of postmenstrual age, unless the infant had been transferred or discharged before that age. In the higher-threshold group, 591 infants completed the treatment per protocol up to 36 weeks, and an additional 137 did so with one or more protocol violations, whereas 183 discontinued treatment early because of death, withdrawal, or transfer or discharge. In the lower-threshold group, 562 infants completed the treatment per protocol up to 36 weeks, an additional 186 did so with one or more protocol violations, and 165 discontinued treatment before 36 weeks. In the higher-threshold group, 23 infants withdrew from the intervention early, of whom 3 had parents who did not consent to their inclusion in subsequent analyses. In the lower-threshold group, 16 infants withdrew from the intervention early, of whom 7 had parents who did not consent to their inclusion in subsequent analyses. Two infants who died before 36 weeks of postmenstrual age also withdrew, but in this figure they were counted as infants who died. Infants with incomplete follow-up included those who presented for the follow-up examination but were missing a key component, usually the cognitive subtest of the Bayley Scales of Infant and Toddler Development assessment (14 infants in the higher-threshold group and 8 infants in the lower-threshold group), and those who did not present for examination but had parents who provided limited questionnaire data (4 and 7 infants, respectively). NDI denotes neurodevelopmental impairment.

Figure 2.. Separation of Hemoglobin Levels between the Treatment Groups.

Hemoglobin levels in the higher-threshold and lower-threshold groups were recorded before enrollment and until 36 weeks of postmenstrual age. Values are means and 95% confidence intervals (indicated by I bars), adjusted for infant as a random effect. Hemoglobin tests were performed at clinical discretion and were not dictated by protocol. Panel A shows the hemoglobin levels that prompted a red-cell transfusion. Panel B shows all hemoglobin levels that were measured in the two groups during the treatment period.