Objectives

To determine whether higher hemoglobin thresholds for red-cell transfusions may reduce the risk of cognitive delay among extremely-low-birth-weight infants.

Background

Long-term outcomes of extremely-low-birth-weight (ELBW) preterm infants, those weighing less than or equal to 1000 g at birth, are poor and pose a major health care burden. ELBW preterm infants are at increased risk of anemia and are commonly treated with transfusions. However, hemoglobin thresholds for transfusion vary because evidence from clinical trials is limited. A post hoc analysis of a one clinical trial suggested that the risk of mild-to-moderate cognitive delay was reduced with higher hemoglobin thresholds.

The Transfusion of Prematures (TOP) trial was initiated to test the hypothesis that a higher hemoglobin threshold for red-cell transfusions, as compared with a lower threshold, would reduce the incidence of death or neurodevelopmental impairment in infants at 22 to 26 months of age, corrected for prematurity.

Participants

Infants with a birth weight of 1000 g or less, a gestational age between 22 weeks 0 days and 28 weeks 6 days, and a postnatal age of 48 hours or less were eligible to participate in the trial. Exclusion criteria included infants with hemorrhage, shock, sepsis or a congenital condition that adversely affected life expectancy or neurodevelopment.

1824 total infants were enrolled. 911 infants were randomly assigned to the higher hemoglobin transfusion threshold group and 913 infants were assigned to the lower hemoglobin transfusion threshold group.

Design

The TOP study was a multicenter randomized trial. Infants were randomly assigned in a 1:1 ratio to receive transfusions at higher or lower hemoglobin thresholds until 36 weeks of postmenstrual age or hospital discharge, whichever occurred first. Randomization was stratified according to birth weight (<750 g or 750 to 1000 g). Multiple-birth siblings underwent randomization individually.

Infants in the higher-threshold group were treated according to a liberal transfusion algorithm, while infants in the lower-threshold group were treated according to a restrictive transfusion algorithm. Hemoglobin transfusion thresholds in both groups were determined according to postnatal age (highest in the first week of life, lower in each of the 2 successive weeks, and stable thereafter) and according to the use of respiratory support (a higher threshold when respiratory support was warranted). Respiratory support was defined as mechanical ventilation, continuous positive airway pressure, a fraction of inspired oxygen (Fio₂) greater than 0.35, or delivery of oxygen or room air by nasal cannula at a flow of 1 liter per minute or more.

The primary outcome was a composite of death or neurodevelopmental impairment in infants at 22 to 26 months of age, corrected for prematurity. Neurodevelopmental impairment was defined as one or more of the following components: cognitive delay (composite cognitive score of less than 85 on the Bayley Scales of Infant and Toddler Development), moderate or severe cerebral palsy (score of level II or higher on the Gross Motor Function Classification System), severe vision loss (less than 20/200 in the better eye), or hearing loss (bilateral hearing loss for which hearing aids or cochlear implants were warranted).

Conclusions

The TOP trial showed that among extremely-low-birth-weight infants, the risk of death or neurodevelopmental impairment at 22 to 26 months of age, corrected for prematurity, was not significantly lower with a higher hemoglobin transfusion threshold level than with a lower hemoglobin transfusion threshold level during the initial hospital course.

Kirpalani H, Bell EF, Hintz SR, et al. Higher or Lower Hemoglobin Transfusion Thresholds for Preterm Infants. N Engl J Med. 2020;383(27):2639-2651. doi:10.1056/NEJMoa2020248

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