Key messages
• Lower and higher haemoglobin thresholds for blood transfusion show similar rates of death or disability at two years.
• A lower threshold does not affect mortality.
• Lower thresholds may result in fewer transfusions.
What is a low blood count?
Anaemia from a low haemoglobin level, or low blood count, is common in very small, premature infants, as small amounts of blood are repeatedly taken for laboratory tests, and also because the bone marrow is slow to respond.
Why does it matter?
A blood transfusion increases the number of red blood cells in the circulation. These cells contain haemoglobin, which carries oxygen around the body. Usually, a blood transfusion is given to improve the amount of oxygen in circulation.
How is a low blood count treated?
Almost all very small, preterm infants receive a blood transfusion due to a low haemoglobin value or blood count. Although blood transfusions are common, we are unsure when transfusions should be given. For this reason, several studies have looked at the risks and benefits of blood transfusion at different blood count values, one called a lower blood count or haemoglobin threshold and one called a higher blood count or haemoglobin threshold.
What did we want to find out?
We wanted to find out if keeping a higher blood count or haemoglobin level by blood transfusion leads to better health and development for very small preterm infants by the time they reach two years of age and if this practice increases the number of transfusions.
What did we do?
We did a comprehensive search for studies that compared blood transfusion with a lower or higher haemoglobin level or blood count threshold in very small, preterm infants.
What did we find?
Six well-designed studies, including 3451 very small, preterm infants, show that infants who were transfused at a lower haemoglobin or blood count threshold did just as well. That is, there was no difference in the rate of either death or disability in survivors, or the combined rate of death and disability compared to infants who were transfused at a higher haemoglobin or blood count threshold. At the same time, infants transfused at a lower haemoglobin or blood count threshold had fewer blood transfusions.
What are the limitations of the evidence?
These large studies show little or no difference in outcomes for very small, preterm infants up to two years of age. The evidence applies only to the haemoglobin levels in the blood count values used in the six studies.
We are confident that a low compared to a high haemoglobin or blood count threshold for transfusion results in little or no difference in health and development for very small, preterm infants by the time they reach two years of age. Our confidence in the evidence for the number of transfusions per infant is low due to a lack of blinding and inconsistency in the results.
How up-to-date is this evidence?
This review updates our previous review (2011). The evidence is up-to-date as of January 2024.
Read the full abstract
Infants of very low birthweight frequently receive red blood cell transfusions during their primary hospital stay. Generally, this is guided by predetermined haemoglobin or haematocrit thresholds according to a protocol or as prompted by clinical situations, including critical illness or surgery. Recommendations advocate maintaining higher thresholds in the early weeks when the risk of major morbidity is highest, while permitting lower thresholds after this time. In truth, clinicians worry about the potential effect of chronic anaemia on neurodevelopmental outcomes, as well as the risk of transfusion-related complications in the immature host.
Clinical trials have reflected this practice by comparing haemoglobin levels adjusted for critical illness, comparing transfusion algorithms that use fixed differences between haemoglobin thresholds, with both thresholds progressively lowered across postnatal age.
This is an update of a review first published in 2011.
Objectives
To evaluate the effect of lower (restrictive) compared with higher (liberal) haemoglobin thresholds for transfusion, with or without adjustment for age and critical illness with either fixed or variable transfusion volume, on mortality or later neurodevelopmental outcomes assessed in later infancy at approximately two years postmenstrual age, or the number of transfusions in very low birthweight infants.
Search strategy
Searches were conducted in January 2024 in CENTRAL, MEDLINE, Embase, CINAHL, Epistemonikos, and trial registries. We searched the reference lists of related systematic reviews and trials.
Selection criteria
We selected randomised controlled trials (RCTs) of lower or restrictive haemoglobin/haematocrit thresholds compared with liberal or higher haemoglobin/haematocrit thresholds for transfusion in low birthweight infants within three days of birth.
Data collection and analysis
We used standard Cochrane methods. Our main outcomes were a combined outcome of death or neurodevelopmental impairment, all-cause mortality, and the number of transfusions per infant. We expressed our results using mean difference (MD), standardised mean difference (SMD), risk ratio (RR), and risk difference (RD) with 95% confidence intervals (CIs). We used GRADE to assess the certainty of evidence.
Main results
Six trials, enrolling 3451 infants, compared transfusion strategies utilising a lower (restrictive) haemoglobin threshold compared to a higher (liberal) haemoglobin threshold. The transfusion thresholds used in these trials reflected prevailing clinical practice at the time of study design. For comparative purposes, they have been labelled as 'restrictive' and 'liberal'.
The trials were similar in design, although each used slightly different transfusion algorithms and intervention thresholds. The three larger trials also conducted later neurosensory assessments. The number of infants included in outcome calculations varies across in-hospital versus post-discharge outcomes, assessment methods, and exclusion criteria, and our analysis uses the denominators reported in the original publications.
Overall, utilising a lower compared to a higher haemoglobin transfusion threshold results in little or no difference in the combined outcome of death or neurodevelopmental impairment at 18 to 26 months postmenstrual age (RR 1.02, 95% CI 0.95 to 1.09; I2 = 55%; RD 0.01, 95% CI -0.03 to 0.04; 3 studies, 3041 infants; high-certainty evidence). Mortality at 18 to 26 months was also not different (RR 0.99, 95% CI 0.83 to 1.17; I2 = 0%; RD -0.00, 95% CI -0.03 to 0.02; I2 = 0%; 3 studies, 3186 infants; high-certainty evidence).
Infants allocated to the restrictive threshold may receive fewer transfusions during the primary hospital stay (mean difference in transfusion number per infant -1.05, 95% CI -1.26 to -0.84; I2 = 84%; 6 studies, 3451 infants; low-certainty evidence).
Authors' conclusions
The trials comparing lower or restrictive versus higher or liberal haemoglobin thresholds for transfusion show little to no difference in important outcomes at hospital discharge and at the time of later neurodevelopmental follow-up. The use of restrictive, as compared to liberal, haemoglobin or haematocrit transfusion thresholds in these trials in infants of very low birthweight results in modest reductions in transfusion exposure and haemoglobin levels.
The safety of haemoglobin levels below these lower limits has not been evaluated and should only be considered in the context of randomised controlled trials.
