Extremely small newborns tolerated a restrictive red blood cell transfusion strategy for anemia in the multicenter TOP trial.
Around 2 years of age, infants had similar rates of either death or survival but with neurodevelopmental impairment (i.e., cognitive delay, cerebral palsy, hearing, or vision loss) whether they had been randomized to higher or lower hemoglobin thresholds for transfusion in the neonatal intensive care unit (NICU) shortly after birth (50.1% vs 49.8%, adjusted RR 1.00, 95% CI 0.92-1.10).
The individual components of death (16.2% vs 15.0%) and neurodevelopmental impairment (39.6% vs 40.3%) were no different between the higher and lower hemoglobin strategies, respectively, according to a group led by Haresh Kirpalani, MD, MSc, of Children’s Hospital of Philadelphia.
“In addition, there was no evidence that the effects of the transfusion strategy on the primary outcome differed according to center, birth-weight group, or sex,” the authors wrote in the New England Journal of Medicine.
Transfusion algorithms tested in the trial were consistent with those used in current practice, as the restrictive strategy still kept hemoglobin levels within clinically accepted ranges, they noted.
“This could be one of the most important studies in our field over the past number of decades. Ever since before I was a medical student, we have debated about whether higher hemoglobin levels and aggressive transfusion strategies were actually better for extremely small babies in the NICU,” commented Lance Prince, MD, PhD, of Stanford University School of Medicine and Lucile Packard Children’s Hospital Stanford in California.
Prince suggested that unlike previous studies yielding mixed results, TOP kept study groups reliably separated given that the higher-threshold group had pre-transfusion hemoglobin levels that were 1.9 g/dL higher on average throughout the treatment period, as well as more transfusions per child (average 6.2 vs 4.4).
“This paper however clearly suggests that allowing lower hemoglobin levels in these critically ill infants (and therefore lower numbers/exposures to blood transfusions) is safe and leads to similar long-term outcomes,” he told MedPage Today in an email.
Another group had reported worse outcomes in newborns receiving preoperative blood transfusions. The evidence generally points to the safety of restrictive transfusion for adults in various settings.
The TOP trial was conducted at 19 centers participating in the Neonatal Research Network of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
Eligible infants were those born with an extremely low birth weight of 1 kg (2.20 lbs) or less and gestational age of 22 to 29 weeks. All were randomized within 48 hours after delivery to red cell transfusions at higher or lower hemoglobin thresholds until 36 weeks of post-menstrual age or discharge (whichever came first).
There were 1,824 babies included in TOP (mean birth weight 756 g [1.67 lbs], mean gestational age 25.9 weeks). Baseline characteristics similar between groups.
Kirpalani and colleagues reported that rates of survival to discharge without severe complications (28.5% vs 30.9%) and serious adverse events (22.7% vs 21.7%) were no different between the liberal and restrictive transfusion strategies.
Notably, the primary endpoint of the trial could be assessed for 92.8% of the cohort at 22-26 months of age due to protocol violations or other reasons.
“For ethical reasons, we could not withhold nonalgorithmic transfusions (i.e., those that were not performed according to the randomly assigned transfusion algorithm), so there was an imbalanced violation rate, with more nonalgorithmic transfusions in the lower-threshold group. This imbalance presumably reflected the unease of some physicians with hemoglobin levels in the lower range,” the TOP team cautioned.
“Nonetheless, the incidence of violations was low and did not preclude good between-group separation in mean hemoglobin levels,” Kirpalani and colleagues maintained.
TOP’s findings are also consistent with the smaller ETTNO trial that recently reported no benefit to a liberal transfusion approach for extremely small infants in the NICU.
The study was funded by grants from the National Heart, Lung, and Blood Institute; the National Institute of Child Health and Human Development; and their cooperative agreements with the National Center for Research Resources and the National Center for Advancing Translational Sciences.
Kirpalani had no disclosures.