1. Low versus high haemoglobin
concentration threshold for blood
transfusion for preventing morbidity and
mortality in very low birth weight infants:
a Cochrane Review
Clinical
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2. Clinical question
• When should we transfuse low birthweight
babies for anemia of prematurity?
Source: Whyte R, Kirpalani H. Low versus high haemoglobin concentration threshold
for blood transfusion for preventing morbidity and mortality in very low birth weight
infants. Cochrane Database of Systematic Reviews 2011, Issue 11. Art. No.: CD000512.
DOI: 10.1002/14651858.CD000512.pub2.
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3. Context
• Haemoglobin levels fall after birth but this is greatly accelerated in
very low birthweight babies.
• In some parts of the world, nearly all babies that weigh under 1000g
at birth receive a blood transfusion, and most receive several.
• Ideally, blood transfusions should be given when the baby’s
haemoglobin reaches the lowest level compatible with health,
safety, and good growth and development. However, this value is
unknown and, so, different strategies are used to decide when to
transfuse.
• Maintaining a high haemoglobin level (liberal strategy) may lead to
excessive repeated transfusion and its complications.
• Maintaining a low haemoglobin level (restrictive strategy) may lead
to cardiac failure, death or neurodevelopmental impairment.
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4. Methods
• Searches were conducted in 2010 and 2011 of the
Cochrane Central Register of Controlled Trials, MEDLINE,
EMBASE and Science Citation Index. Prospectively
registered trials were searched for in the U.S. National
Institutes of Health’s Clinicaltrials.gov and conference
proceedings were checked for unpublished trials.
• Data were extracted on the inclusiveness of the
population, masking of allocation, masking of intervention,
completeness of follow-up and masking of outcome
assessment.
• Meta-analyses used the random effects model because of
marked clinical and, often, statistical heterogeneity.
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5. PICO(S) to assess eligible studies
• Participants: Infants of <1500 g birthweight or <32 weeks
gestational age; who were less than 1 week old and receiving any
level of intensive care.
• Comparison 1: Restrictive versus liberal transfusion protocols (i.e.
low haemoglobin threshold versus high haemoglobin threshold for
transfusion).
• Comparison 2: Restrictive versus liberal strategy (i.e. withhold
transfusion until clinical signs of anaemia versus administer earlier
transfusion at a set level of haemoglobin or haematocrit).
• Primary outcomes: Death before a defined time, composite of
death or severe morbidity, and composite of death or severe
adverse neurosensory outcome at age 18 months.
• Studies: Randomized and quasi-randomized trials.
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6. Description of eligible studies
• Four studies with a total of 651 infants were included in
comparison 1 (restrictive versus liberal transfusion
protocols), with three reporting a primary outcome of
numbers of transfusions (a secondary outcome for this
review) and one reporting a primary outcome of death or
serious adverse outcome.
• One study (56 infants) was included in comparison 2
(restrictive versus liberal strategy). It reported clinical
events up to discharge, but did not report death or
serious morbidity.
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7. Results: comparison 1
• There were no significant differences between the
transfusion protocols on death (see slide), death or
severe morbidity at hospital discharge, or death or
impaired neurodevelopmental outcome at 18-21 months.
• Restrictive transfusion protocols led to a small decrease
in transfusion frequency and haemoglobin levels
compared to liberal transfusion protocols. The relative
risk for transfusion was 0.95 (95% confidence interval:
0.91-1.00, p=0.041) and the mean number of
transfusions per baby was 1.12 lower (95% CI:
0.49-1.75, p<0.001).
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8. Comparison 1: Death before discharge
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9. Results: comparison 1
Cognitive function
• In the one study that reported neurosensory impairment
at 18-21 months of age, the effect on cognitive function
was close to favoring the liberal strategy in an unadjusted
analysis of the originally planned outcome (RR: 1.39;
0.90-2.13), and statistically significantly better when a
less severe definition cognitive function was used (RR:
1.32; 1.00-1.74).
• This apparent benefit of the liberal strategy was
strengthened when the original researchers adjusted
their analysis for gestational age (RR: 1.28; 0.84-1.94
and 1.37; 1.07-1.76, respectively).
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10. Comparison 1: Neurosensory impairment
at 18-21 months in survivors
Cognitive delay MDI < 70
Unadjusted RR: 1.39 (0.90-2.13)
Adjusted RR: 1.28 (0.84-1.94)
Cognitive delay MDI < 85
Unadjusted RR: 1.32 (1.00-1.74)
Adjusted RR: 1.37 (1.07-1.76)
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11. Results: comparison 2
• There were no significant differences in short-term health outcomes,
when clinical findings rather than haemoglobin levels were used to
drive transfusions.
Topped up at Clinical
Effect (95% Cl)
100 g/l signs
Death or death / morbidity Not reported
Infants with apnea 17/26 19/30 RR 0.97 (0.66 to1.43)
Time to regain birthweight 26 days 27 days MD 1 (-5 to 6)
Length of hospitalization 51 days 49 days MD -2 (-13 to 9)
Hospital costs $3430 $3642 MD $212 (446 to 870)
Discharge haemoglobin 118 g/l 91 g/l MD -26 g/l (-35 to -17)
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12. Conclusions
• The use of restrictive as compared to liberal haemoglobin
transfusion thresholds in very low birthweight infants results in
modest reductions in exposure to transfusion and in haemoglobin
levels.
• There is no evidence that using a lower haemoglobin transfusion
threshold (using the limits tested in these trials) has an effect on
mortality, major morbidities or on survival without major morbidity
in very low birth weight infants.
• As the restrictive levels used were more similar among trials, a
summarised approximation of the lower thresholds evaluated is
presented in the following table. Safety at haemoglobin levels
below these lower limits has not been evaluated and these should
be maintained until further evidence is available.
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13. Approximate lower limits for haemoglobin and
haematocrit thresholds evaluated in this review
Postnatal age Respiratory No respiratory
support support
Haemoglobin g/l (Haematocrit %)
<7 days 115 (35%) 100 (30%)
7-14 days 100 (30%) 85 (25%)
14-21 days 85 (25%) 75 (23%)
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