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Author:
Joseph A Garcia-Prats, MD
Section Editors:
Steven A Abrams, MD
Donald H Mahoney, Jr, MD
Deputy Editor:
Melanie S Kim, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review
process is complete.
Literature review current through: Dec 2016. | This topic last updated: Oct 27,
2015.
INTRODUCTION Erythropoiesis decreases after birth as a result of increased tissue
oxygenation due to the onset of breathing and closure of the ductus arteriosus, and a
reduced production of erythropoietin (EPO) [1]. In term infants, the hemoglobin level
typically reaches an average nadir of 11 g/dL at approximately 8 to 12 weeks after
birth.
In preterm infants who are already born with a lower hematocrit, this decline, referred
to as anemia of prematurity (AOP), occurs earlier and is more pronounced in its
severity than the anemia seen in term infants. The AOP will be reviewed here.
PATHOGENESIS The primary cause of anemia of prematurity (AOP) is the impaired
ability to increase serum erythropoietin (EPO) appropriately in the setting of anemia
and decreased tissue availability of oxygen [2,3]. Circulating and bone marrow red cell
progenitors respond to EPO, if present, indicating that the impaired erythropoiesis is
due to lack of EPO, not a failure to respond to the hormone [4-6]. Other hematopoietic
growth factors (eg, granulocyte-macrophage colony-stimulating factor) are not affected.
Impaired erythropoietin production EPO is produced by the fetal liver and the
cortical interstitial cells of the kidney in response to hypoxia. Its production is regulated
by the transcription factor hypoxia inducible factor-1 (HIF-1). Its primary function is to
regulate erythrocyte production. EPO does not cross the placenta in humans, and fetal
production increases with gestational age [7-10].
Production of EPO in adults depends on the oxygen saturation of hemoglobin and
tissue oxygen delivery, and is inversely proportional to central venous oxygenation.
Although EPO levels in preterm infants with AOP increase slightly with hypoxia, they
are lower than those seen in older children and adults with the same level of anemia
[2,11]. (See "Regulation of erythropoiesis".)
In AOP, the specific mechanisms leading to the discrepancy between serum EPO
concentration and the severity of the anemia are uncertain. Proposed pathogenetic
pathways involve the site of EPO production and the developmental regulation of
transcription factors in the liver versus the kidney.
The liver is the principal site of EPO production in the fetus [12,13]. The
feedback increase in hepatic EPO mRNA in response to anemia or hypoxia may
be less than that of the kidney [14]. EPO mRNA expression in the kidney is
present in the fetus, and increases significantly after 30 weeks gestation,
suggesting that the switch to the kidney as the main site of EPO production is
developmentally regulated.
The fetal or neonatal environment may alter the response to hypoxic signals by
the liver. Support for this hypothesis comes from the observation that hepatic
transplantation from fetal and neonatal lambs into adult sheep increased EPO
production by the transplanted liver [15].
Transcriptional regulatory factors, such as HIF-1, may contribute to low levels of
EPO in premature infants. These factors activate target genes, including those
encoding EPO, in response to decreased cellular oxygen concentration [16,17].
They appear to be developmentally regulated in some fetal tissues, which might
account for the decreased expression of EPO in response to anemia in preterm
infants [1,18].
Other factors Although AOP is directly due to impaired EPO production, several
other factors can contribute to anemia in preterm infants, including blood loss from
phlebotomy, reduced red blood cell life span, and iron depletion.
Blood loss from phlebotomy Premature infants frequently develop an early
anemia that is primarily due to iatrogenic blood loss due to phlebotomy for blood tests.
The volume of blood loss increases with illness severity and decreasing gestational
age. In one report, withdrawal of blood in excess of that required for laboratory studies
contributed to iatrogenic blood loss by 2 to 4 mL/kg per week [19]. However, efforts to
reduce blood loss from phlebotomy have resulted in changes in clinical practice to limit
blood sampling for essential testing and the use of microtechniques, which have
reduced iatrogenic blood loss.
The impact of clinical practice on phlebotomy and blood testing was illustrated in a
study of very low birth weight (VLBW) infants (birth weight <1500 g) cared for in two
neonatal intensive care units (NICUs) [20]. Phlebotomy losses increased with
decreasing gestational age and increasing illness severity, as measured by the Score
for Neonatal Acute Physiology (SNAP). The average losses due to phlebotomy differed
between the two NICUs and resulted in increased average blood transfusion
requirements in the NICU with the greater volume of blood loss. However, this
difference was not associated with differences in the days of oxygen therapy or
mechanical ventilation, risk of bronchopulmonary dysplasia, or growth rate by day 28 of
life. These findings suggest that the additional use of blood in one of the NICUs was
discretionary rather than necessary, as clinical outcomes did not differ.
These studies indicate that blood loss due to phlebotomy in preterm infants may be
greater than is necessary for the care of the neonate. They emphasize the need for
nursery policies to ensure that only the minimal volume required for testing is drawn,
and unnecessary tests are avoided.
Reduced red blood cell life span Red blood cell survival in newborn term infants is
approximately 60 to 80 days, but decreases with decreasing gestational age to a range
of 45 to 50 days in extremely low birth weight infants (ELBW) (birth weight below 1000
g) [21]. The reduced red cell life span contributes to the severity of anemia. Increased
susceptibility to oxidant injury may contribute to shortened red cell survival in the
neonate [22,23]. (See "Red blood cell survival: Normal values and measurement".)
Iron depletion Although it is not involved in its pathogenesis, iron depletion may
impair recovery from AOP. Because of their rapid growth rate, premature infants have
increased utilization and depletion of iron stores and, as noted above, blood loss from
phlebotomy. The administration of iron does not inhibit the fall in hemoglobin
concentration due to AOP. However, in term infants, it reduces the incidence of iron
deficiency anemia in the first year of life [2]. (See "Iron deficiency in infants and young
children: Screening, prevention, clinical manifestations, and diagnosis".)
Low levels of other nutrients, such as vitamin B12 or folate, do not appear to contribute
to neonatal anemia [1]. In one randomized trial, the combination of folate, vitamin B12,
iron, and EPO compared with control therapy improved the ELBW infant's chance of
remaining transfusion free (38 versus 5 percent) [24].
OXYGEN DELIVERY Oxygen delivery is the rate at which oxygen is transported
from the lungs to the microcirculation. It is determined by the product of cardiac output
and arterial oxygen content. The arterial oxygen content is the amount of oxygen
bound to hemoglobin plus the amount of oxygen dissolved in arterial blood.
(See "Oxygen delivery and consumption".)
Oxygen delivery is dependent upon:
Cardiac output
Hemoglobin concentration
Oxygen carrying capacity (affinity) of hemoglobin
Arterial oxygen saturation and oxygen tension
In preterm infants with anemia, physiologic changes, which aim at maintaining
adequate oxygen delivery, compensate for a significant decrease in hemoglobin, and
are similar to those seen in older children and adults. These include increases in heart
rate and stroke volume, which improve cardiac output [25].
However, anemic preterm infants may be less able to maintain oxygen delivery
because of the following:
Concomitant respiratory disease, such as respiratory distress syndrome and
bronchopulmonary dysplasia, resulting in hypoxia.
Limitations on maximum arterial oxygen saturation and oxygen tension for
infants requiring respiratory support, because hyperoxia increases the risk of
bronchopulmonary dysplasia and retinopathy of prematurity. (See "Pathogenesis
and clinical features of bronchopulmonary dysplasia", section on 'Oxygen
The reticulocyte count is low, and red blood cell precursors in the bone marrow
are decreased [2].
Serum concentrations of erythropoietin (EPO) are low in premature infants
during the first postnatal month compared with adults (9.7 versus
15.2 mU/mL) and remain inappropriately low for the extent of anemia through the
second postnatal month [3].
MANAGEMENT Clinicians who care for premature infants should anticipate the
development of anemia of prematurity (AOP). Optimal nutrition (eg, iron
supplementation) should be provided and patients monitored for signs of anemia.
Blood sampling should be limited to essential testing, and microtechniques should be
used to minimize blood loss due to phlebotomy [19,35]. (See 'Blood loss from
phlebotomy' above.)
Red blood cell transfusions are primarily used to treat infants with AOP. Human
erythropoietin (EPO) appears to have limited benefit in decreasing exposure to different
blood donors and is NOT recommended for routine use.
Iron supplementation The iron content at birth is lower in preterm infants than in
term infants, and the iron stores of preterm infants often are depleted by two to three
months of age. As a result, all preterm infants who are breastfed should receive iron
supplementation of 2 to 4 mg/kg per day through the first year of life [36]. Infants who
receive iron-fortified formula need less additional supplementation than those who are
exclusively breastfed, because for a given volume, iron-containing formula contains a
higher concentration of iron than breast milk. Low iron-containing preterm formulas
should not be used as they do not adequately provide the necessary iron required for
these patients. (See "Iron deficiency in infants and young children: Screening,
prevention, clinical manifestations, and diagnosis".)
Although iron supplementation does not prevent AOP, the use of iron-fortified formula
compared with nonfortified formula allows for greater iron substrate when
erythropoiesis is stimulated [37]. Iron supplementation does reduce iron-deficiency
anemia, which both premature and term infants are at high risk for developing in the
first year of life. (See "Nutritional composition of human milk and preterm formula for
the premature infant" and "Iron deficiency in infants and young children: Screening,
prevention, clinical manifestations, and diagnosis".)
Laboratory monitoring The hematocrit (HCT) or hemoglobin (Hb) concentration
should be monitored on a weekly basis in extremely low birth weight (ELBW) infants
(birth weight less than 1000 g) in the first weeks of life. Thereafter, in healthy, growing
premature infants, it is not necessary to routinely monitor HCT/Hb. Infants with
persistent illness (eg, bronchopulmonary dysplasia) or surgical issues may require
monitoring.
In asymptomatic infants, measuring a reticulocyte count at approximately four to six
weeks after birth is used to evaluate whether a red blood cell (RBC) transfusion may be
needed. Although no clearly defined biological markers have been identified to indicate
secondary outcomes evaluated [39]. In addition, the subanalysis that reported early
administration resulted in an increased risk of severe ROP must be interpreted with
caution, given that the overall effect on all grades of ROP was substantially lower.
Among the studies included in the analysis, there were no data regarding the
gestational age of the patients and illness severity, which both directly have an impact
on the risk of ROP. Further studies are required to demonstrate whether or not there is
a clinically significant association between early EPO use and ROP.
Although it is difficult to determine the role of EPO in the multifactorial pathogenesis of
ROP, the current evidence is sufficient to raise concerns about the early use of EPO
given the limited benefit of reducing exposure to blood donors, its cost, and potential
association with ROP. As a result, we recommend NOT to routinely administer EPO
within the first eight days of life.
Late EPO use Late administration of EPO reduces the number of transfusions, but
the limited benefit does not justify its use. This was illustrated in a 2014 meta-analysis
that evaluated the effects of late EPO administration (at or later than eight days of age)
compared with placebo or no intervention [42]. Most of these infants had received
blood transfusions prior to enrollment in the trials. The following findings were noted:
EPO reduced the risk of receiving one or more red blood cell transfusions (RR
0.71, 95% CI 0.64-0.79).
EPO reduced the number of red blood cell transfusions (weighted mean
difference of -0.22, 95% CI -0.38 to -0.06).
There was no difference in the volume of blood transfused (mean difference
-1.6 mL/kg, 95% CI -5.8 to 2.6).
EPO had no effect on the rates for ROP, mortality, sepsis, intraventricular
hemorrhage (IVH), periventricular leukomalacia (PVL), necrotizing enterocolitis
(NEC), bronchopulmonary dysplasia (BPD), hypertension, length of hospital stay,
or long-term neurodevelopmental outcome. However, there was a trend towards
an increased risk of ROP associated with EPO administration (RR 1.27, 95% CI
0.99-1.64).
Late administration of EPO reduced the mean number of transfusions by a little less
than one transfusion per infant. This small benefit of EPO was diminished due to the
exposure of previous blood transfusions before eight days of life, and the use of
satellite packs that would mitigate against additional donor exposure in the control
group. As a result, we recommend NOT to routinely administer EPO after eight days
because its limited benefit of limiting exposure to blood donors does not justify its cost.
Comparison early versus late use There appears to be no benefit of early EPO
administration compared with late administration in reducing the number of
transfusions, the amount of red cells transfused, or number of donor exposures per
infant. This was illustrated in a meta-analysis of two trials (262 patients), which was
updated in 2012, that found no statistical benefit of early EPO administration [43,44].
However, there appeared to be an increased risk of ROP associated with early
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