Definition

1. 
   

   Anemia that develops in the neonatal period in term infants is typically defined by central venous hemoglobin of less than 13 g/dL or capillary hemoglobin of <14.5 g/dL.

   
   
2. 
   

   In healthy term infants, the nadir hemoglobin value rarely falls below 10 g/dL at an age of 10 to 12 weeks. Because this postnatal drop in hemoglobin level in term infants is well tolerated and requires no therapy, it is commonly referred to as the physiological anemia of infancy.

   
   
3. 
   

   In contrast, this decline is more rapid (ie, nadir at 4 to 6 weeks of age) and the blood hemoglobin concentration falls to lower levels in infants born prematurely—to approximately 8 g/dL in infants with birthweights of 1.0 to 1.5 kg and approximately 7 g/dL in infants with birthweights <1 kg.

   
   
4. 
   

   Consequently, because the pronounced decline in hemoglobin concentration that occurs in many ELBW infants is associated with abnormal clinical signs and need for allogeneic RBC transfusions, the anemia of prematurity is not accepted to be a physiological and benign event.

   
   
5. 
   

   Physiologic and nonphysiologic factors related to prematurity are responsible for the anemia of prematurity, though there are no specific hemoglobin values defining the condition in preterm populations.

Incidence

1. 
   

   All healthy, term newborn infants have a high blood hemoglobin level (15 to 20 g/dL) at birth due to relative hypoxia in utero.

   
   
2. 
   

   Some extremely preterm neonates will have slightly lower values than term infants (eg, 13 g/dL), and occasional neonates will have higher values (eg, 22 g/dL).

   
   
3. 
   

   Regardless of the level at birth, all experience a fall in hemoglobin levels over the first weeks of life, with term infants reaching a nadir level of about 11.5 g/dL at 12 weeks of life. In contrast, preterm infants experience a more profound and rapid drop in hemoglobin levels, which may result in severe anemia requiring red blood cell (RBC) transfusions.

   
   
4. 
   

   Approximately 90% of ELBW neonates will receive at least one RBC transfusion, typically during the first weeks of life.

   
   
5. 
   

   Because of efforts to minimize the amounts of blood drawn from neonates for laboratory testing and to transfuse more conservatively (ie, to accept lower pretransfusion hematocrit [HCT] values), the number of RBC transfusions given to preterm infants has dropped over the years.

Pathophysiology

Several physiological factors play a role in the pathogenesis of the anemia of prematurity.

1. 
   

   All neonates experience a decline in circulating RBCs during the first weeks of life. This decline results both from multiple physiological factors and, in sick preterm infants, from several additional factors—the major one being phlebotomy blood losses for laboratory testing.

   
   
2. 
   

   Because ELBW infants are born before the third trimester of gestation, they are deprived of most of the iron transported from the mother and miss out on a great deal of in utero fetal erythropoiesis.

   
   
3. 
   

   Extrauterine body growth is extremely rapid during the first months of life, and RBC production by neonatal marrow must increase commensurately.

   
   
4. 
   

   It is widely accepted that the circulating life span of neonatal RBCs in the bloodstream is shorter than that of adult RBCs due to several developmental differences in metabolic and membrane characteristics of neonatal RBCs compared to RBCs from adults. However, circulating RBC lifespan is difficult to measure accurately because studies of transfused autologous (neonatal or placental) RBCs labeled with biotin or radioactive chromium may underestimate RBC survival in the infant’s bloodstream for technical reasons.

   
   
5. 
   

   Low plasma erythropoietin levels

   
   
   
   
   1. 
      

      A key reason that the hemoglobin nadir is lower in a preterm than in a term infant is the former group’s diminished plasma erythropoietin (EPO) level in response to anemia.

      
      
   2. 
      

      Although anemia provokes EPO production in premature infants, the plasma levels achieved in anemic infants, at any given HCT value, are lower than those observed in comparably anemic older persons.

      
      
   3. 
      

      Erythroid progenitor cells of newborn infants are quite responsive to EPO in vitro—a finding suggesting that it is the low level of EPO that is, at least, one major cause of neonatal anemia, not marrow unresponsiveness.

      
      
   4. 
      

      One mechanism is that the primary site of EPO production in preterm infants is in the liver, rather than the kidney. This dependency on hepatic EPO is important because the liver is relatively insensitive to anemia and tissue hypoxia—hence, there is a relatively sluggish EPO response (ie, diminished production) to the infant’s falling HCT level. The timing of the switch from the liver to kidney as the primary site for EPO production is set at conception and cannot be accelerated to compensate for preterm birth.

      
      
   5. 
      

      Diminished EPO production cannot entirely explain low plasma EPO levels in anemic infants because extraordinarily high plasma levels of EPO have been reported in some fetuses and infants.

      
      
   6. 
      

      Accelerated catabolism compounds the problem of diminished EPO production, so that the low plasma EPO levels are a combined effect of decreased synthesis plus increased catabolism/metabolism.

   
   
6. 
   

   Phlebotomy

   
   
   
   
   1. 
      

      Blood losses from lab testing play a key role in the anemia of prematurity and in the need for RBC transfusions—particularly, during the first few weeks of life.

      
      
   2. 
      

      The modern practice of neonatology requires critically ill neonates to be monitored closely with serial laboratory studies such as blood gases, electrolytes, blood counts, and cultures.

      
      
   3. 
      

      Small preterm infants are the most critically ill—hence, they require the most frequent blood sampling and suffer the greatest proportional loss of RBCs because their circulating RBC volumes are smallest.

      
      
   4. 
      

      The mean volume of blood removed for sampling has been reported to range from 0.8 to 3.1 mL/kg/d during the first few weeks of life for preterm infants requiring intensive care.

      
      
   5. 
      

      Promising “in-line” devices that withdraw blood, measure multiple analytes, and then reinfuse most of the sampled blood have been reported. They have decreased the need for RBC transfusions. However, until these devices are proven more extensively to be feasible, cost effective, clinically efficacious, and safe, replacement of blood losses due to phlebotomy will remain a key factor responsible for RBC transfusions given to critically ill neonates—particularly, transfusions given during the first four weeks of life.

      
      
   6. 
      

      Meanwhile, it is critical to limit testing to only those tests absolutely needed for optimal care and to avoid overdraw (ie, taking more infant blood than actually needed).

Risk factors

1. 
   

   Lower birthweight

   
   
2. 
   

   Lower birth gestational age

   
   
3. 
   

   Severity of illness (sepsis, NEC, IVH, etc)

   
   
4. 
   

   Presence of any number of causes of hemorrhagic or hemolytic anemia

Clinical presentation

1. 
   

   Pallor

   
   
2. 
   

   Jaundice

   
   
3. 
   

   Tachypnea

   
   
4. 
   

   Hypoxia and/or increased need for respiratory support

   
   
5. 
   

   Tachycardia

   
   
6. 
   

   Apnea, periodic breathing, and/or bradycardia

   
   
7. 
   

   Heart murmur

   
   
8. 
   

   Hepatomegaly

   
   
9. 
   

   Poor feeding

   
   
10. 
    

    Poor growth

Diagnosis

1. 
   

   Hemoglobin (venous or capillary)

   
   
2. 
   

   Reticulocyte count

Management

1. 
   

   Nutritional supplements

   
   
   
   
   1. 
      

      Iron

      
      
      
      
      • 
        

        Start supplementation of 1 to 2 mg/kg/d of elemental iron at about 1 month, if on full feeds, and continue until 1 year corrected age.

        
        
      • 
        

        This may be increased up to 6 mg/kg/d (including amount present in infant formula) with significant anemia and tolerating enteral feeds.

        
        
      • 
        

        150 mL/kg/d of iron fortified infant formula provides about 2 mg/kg/d of elemental iron.

        
        
      • 
        

        1 mL of infant multivitamin generally contains 10 mg of elemental iron.

        
        
      • 
        

        Hold iron supplements for about 2 weeks posttransfusion.

      
      
   2. 
      

      Vitamin E

      
      
      
      
      • 
        

        Consider supplementing with 25 IU/d.

   
   
2. 
   

   Recombinant human erythropoietin

   
   
   
   
   1. 
      

      Although a great deal of logic exists to suggest a rationale for recombinant human EPO therapy, its use is very limited, and the mainstay of treatment for the anemia of prematurity is small-volume RBC transfusions.

      
      
   2. 
      

      Has been shown to reduce the need for late transfusions, after 2 to 3 weeks of life.

      
      
   3. 
      

      When combined with restrictive blood sampling and a unit transfusion protocol, the need for transfusions in the NICU can be greatly reduced.

      
      
   4. 
      

      Early administration of EPO

      
      
      
      
      • 
        

        1200 to 1400 U/kg/wk is added to TPN beginning on the first few days of life.

      
      
   5. 
      

      Late administration of EPO

      
      
      
      
      • 
        

        500 to 700 U/kg/wk is given by subcutaneous injection three to five times weekly.

      
      
   6. 
      

      Iron supplementation must be given along with EPO therapy in order to maximize effect.

   
   
3. 
   

   Transfusion

   
   
   
   
   1. 
      

      Guidelines for transfusing RBCs to preterm neonates are controversial, and practices vary greatly.

      
      
   2. 
      

      Generally, RBC transfusions are given to maintain a level of blood hemoglobin or HCT believed to be optimal for each neonate’s clinical condition.

      
      
   3. 
      

      Guidelines for RBC transfusions, judged to be reasonable by most neonatologists to treat the anemia of prematurity, are listed in Table 17-1 These guidelines are very general, and it is important that terms such as severe and symptomatic be defined to fit local transfusion practices/policies.

      
      
   4. 
      

      Importantly, guidelines are not mandates for RBC transfusions that must be followed; they simply suggest situations when an RBC transfusion would be judged to be reasonable/acceptable.

      
      
   5. 
      

      Restricted versus liberal guidelines

      
      
      
      
      • 
        

        An important controversy that is still unresolved is whether or not prescribing RBC transfusions to neonates using restricted (RES) guidelines (ie, permitting HCT values to fall to relatively low pretransfusion levels before giving an RBC transfusion) versus liberal (LIB) guidelines (ie, relatively high pretransfusion HCT values) is most beneficial.

        
        
      • 
        

        Studies found that neonates in the RES group received fewer RBC transfusions, without an increase in mortality or morbidity as assessed by most clinical outcomes. However, follow-up may show worse neurologic outcomes in the restricted group.

        
        
      • 
        

        Without consensus, it seems wise to transfuse preterm neonates using conventional, not greatly restrictive or greatly liberal guidelines (ie, do not place infants at possible risks of either under- or overtransfusion).

      
      
   6. 
      

      The vast majority of RBC transfusions given to ELBW infants are small volume and consist of 10 to 20 mL/kg (infant’s weight on the day of transfusion) of allogeneic RBCs stored in preservative solution at an HCT of ∼60% (42-day storage permitted in modern additive AS-1, AS-3, AS-5 solutions) or ~70% (35-day storage permitted in older CPDA solution).

      
      
   7. 
      

      The quantities/doses of additives transfused with small volumes of AS-1, AS-3, or AS-5 RBCs are extremely modest compared to estimated toxic doses (Table 17-2) and, importantly, multiple clinical trials have documented both efficacy and safety of RBCs stored in additive solutions when transfused into infants.

      
      
   8. 
      

      Most RBC transfusions given to infants are prescribed to treat the anemia of prematurity and consist of 15 ± 5 mL/kg RBCs infused over 2 to 4 hours.

      
      
   9. 
      

      The historical practice to transfuse only fresh RBCs (<7 days of storage) has been replaced in most centers by the practice of transfusing aliquots of RBCs from a dedicated unit of RBCs stored up to 42 days, as a means to diminish the high donor exposure rates among infants who undergo numerous transfusions.

      
      
   10. 
       

       It is universally accepted that measures be taken to prevent transfusion-transmitted cytomegalovirus (CMV) infections, and considerable evidence exists to support leukocyte reduction, when done under controlled conditions by the blood supplier/center (ie, not at the bedside), as being the best available technique to prevent transfusion-transmitted CMV with nearly 100% efficacy.

       
       
   11. 
       

       Posttransfusion graft-versus-host disease during infancy occurs almost exclusively in infants with underlying disorders of cell-mediated immunodeficiency, following intrauterine and/or exchange transfusions, or when they are transfused with blood from blood relatives. Graft-versus-host disease occurring outside of these clinical settings is extremely rare (ie, arising in infants who are healthy except for being premature). Nonetheless, most preterm infants transfused in the United States receive irradiated blood components as a routine.

Prognosis

1. 
   

   Anemia of prematurity universally resolves.

   
   
2. 
   

   Timing

   
   
   
   
   1. 
      

      Anemia of prematurity usually resolves by 3 to 4 months of age, depending on ongoing blood sampling, gestational age and size at birth, and degree of illness.

      
      
   2. 
      

      As such, late preterm and moderately preterm infants may be ready for discharge prior to their anemia of prematurity resolving.

      
      
   3. 
      

      Recent transfusions will prolong the process.

      
      
   4. 
      

      The HCT must drop to a certain level before erythropoiesis is stimulated. Thus, if the convalescing very preterm infant has asymptomatic anemia, a low HCT may be beneficial resolving anemia of prematurity.

Discharge

1. 
   

   Teaching

   
   
   
   
   1. 
      

      Parents should be told their child’s level of anemia at discharge (many have heard the word hematocrit and follow the number during their NICU stay) and understand their infant’s risk for becoming symptomatic of anemia after discharge.

      
      
   2. 
      

      Often parents worry about the need for transfusion and they should be reassured that it is very rare for preterm infants to require a blood transfusion for anemia of prematurity postdischarge.

      
      
   3. 
      

      Parents should be taught symptoms of anemia (pale, breathing fast, poor feeding, poor alertness) to observe for at home.

      
      
   4. 
      

      Parents should learn how to administer iron supplementation and be taught the importance of giving to their infant.

   
   
2. 
   

   Monitoring

   
   
   
   
   1. 
      

      Hematocrit and reticulocyte count should be assessed within 1 week of discharge.

   
   
3. 
   

   Safety

   
   
   
   
   1. 
      

      Parents should be instructed to notify their pediatrician if their child becomes symptomatic of anemia.