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Anemia of Prematurity: Treatment & Medication

Author: Charles F Potter, MD, Consulting Neonatologist, Newborn Care Physicians of Southeastern Wisconsin
Coauthor(s): W Michael Southgate, MD, Professor of Pediatrics, Pediatrics Program Director, Medical University of South Carolina
Contributor Information and Disclosures

Updated: Jan 15, 2009

Treatment

Medical Care

The medical care options available to the clinician treating an infant with anemia of prematurity (AOP) are prevention, blood transfusion, recombinant erythropoietin (EPO) treatment or observation.

Prevention

• Reducing the amount of blood taken from the premature infant diminishes the need to replace blood. When caring for the premature infant, carefully consider the need for each laboratory study obtained. Hospitals that care for premature infants should have the ability to determine laboratory values using very small volumes of serum.
• Manufacturers are developing an array of technologies that require extremely small amounts of blood for a steadily increasing number of tests. Likewise, devices that allow blood gases and serum chemistries to be determined at bedside via an analyzer attached to the umbilical artery catheter without loss of blood have been developed. The impact of such devices on the development of anemia and/or the need for transfusions has yet to be determined.
• The use of noninvasive monitoring devices, such as transcutaneous hemoglobin oxygen saturation, partial pressure of oxygen, and partial pressure of carbon dioxide, may allow clinicians to decrease blood drawing; however, no data currently support such an impact of these devices.

Blood transfusion

• Packed red blood cell (PRBC) transfusions: Despite disagreement regarding timing and efficacy, PRBC transfusions continue to be the mainstay of therapy for the individual with AOP. The frequency of blood transfusions varies with gestational age, degree of illness, and, interestingly, the hospital evaluated. The decision to give a transfusion should not be made lightly because significant infectious, hematologic, immunologic, and metabolic complications are recognized. Late-onset necrotizing enterocolitis has been reported in stable-growing premature infants electively transfused for AOP. Transfusions also transiently decrease erythropoiesis and EPO levels, but this effect is not sustained.
• Reducing the number of transfusions: Studies derived from individual centers document a marked decrease in the administration of PRBC transfusions over the past 2 decades, even before the use of EPO. This decrease in transfusions is almost certainly multifactorial in origin. One frequently mentioned component is the adoption of transfusion protocols that take various factors into account, including hemoglobin levels, degree of cardiorespiratory disease, and traditional signs and symptoms of pathologic anemia. A restricted transfusion protocol may decrease the number of transfusions while also decreasing the hematocrit at discharge.
• The Premature Infant in Need of Transfusion (PINT) study demonstrated that transfusing infants to maintain a high hemoglobin level (8.5-13.5 g/dL) confers no benefit in terms of mortality, severe morbidity, or apnea intervention compared with infants transfused to maintain a low hemoglobin level (7.5-11.5 g/dL).¹ This differs from the Iowa study, which found less parenchymal brain hemorrhage, periventricular leukomalacia, and apnea in infants whose transfusion criteria was not restricted and whose hemoglobin level was higher. Clearly, no set guidelines for transfusion in infants with AOP are prescribed, and clinicians must determine a reasonable transfusion practice.
• Although transfusion guidelines are suggested to reduce the number of transfusions performed in a neonatal ICU (NICU), exact criteria or hemoglobin (Hb) and hematocrit (Hct) values at which to transfuse remain controversial. The Children's Hospital of Wisconsin Transfusion Committee uses the following clinical circumstances to review transfusions for infants:
  • An infant with a Hb level of less than 8 g/dL may be transfused at the discretion of the attending physician.
  • A stable infant with a Hb level of 8-10 g/dL without clinical evidence of anemia (tachycardia, tachypnea, poor feeding) or other exceptions listed below may be transfused.
  • An infant with a Hb level of 11-13 g/dL without a supplemental oxygen or continuous positive airway pressure (CPAP) requirement, apnea/bradycardia, significant tachycardia or tachypnea, or other exceptions listed below may be transfused.
  • An infant with a Hb level of more than 13 g/dL without an oxygen requirement of more than 40% by hood, CPAP, or ventilator; hypotension that requires pressor medication; major surgery; or other exceptions listed below may be transfused.
  • An infant with a Hb level of more than 15 g/dL without cyanotic heart disease, extracorporeal membrane oxygenation (ECMO) therapy, regional oxygen saturations less than 50%, or hypotension that requires pressor medications may be transfused.
  • An infant with a history of massive blood loss may be transfused at the discretion of the attending physician.

Observation

In infants who are asymptomatic, no longer acutely ill, and receiving adequate nutrition, including sufficient iron and other vitamins, observation may be the best course of action.

Reducing the number of donor exposures

In addition to reducing the number of transfusions, reducing the number of donor exposures is important. This can be accomplished as follows:

• Use PRBCs stored in preservatives (eg, citrate-phosphate-dextrose-adenine [CPDA-1]) and additive systems (eg, Adsol). Preservatives and additive systems allow blood to be stored safely for as long as 35-42 days. Infants may be assigned a specific unit of blood, which may suffice for treatment during their entire hospitalization and limit exposure to a single donor. Concerns that stored blood might increase serum potassium levels are unfounded, if the transfused volume is low.
• Use volunteer-donated blood and all available screening techniques. The risk of cytomegalovirus (CMV) transmission can be dramatically reduced (but not entirely) through the use of CMV-safe blood. This can be accomplished by using CMV serology-negative cells along with blood processed through leukocyte-reduction filters or inverted spin technique. These latter 2 methods also reduce other WBC-associated infectious agents (eg, Epstein-Barr virus, retroviruses, Yersinia enterocolitica) by yielding a leukocyte poor suspension of PRBCs. The American Red Cross is now providing exclusively leukocyte-reduced blood to hospitals in the United States.

Recombinant erythropoietin treatment

• Multiple investigations have established that premature infants respond to exogenously administered recombinant human EPO and supplemental iron with a brisk reticulocytosis. Subcutaneous administration of EPO may be preferred as intravenous administration has increased urinary losses. Although EPO cannot prevent early transfusions, modest decreases in the frequency of late PRBC transfusions have been documented. Additional iron supplementation is necessary during exogenous EPO treatment.
• Trials have evaluated the impact of EPO treatment in populations of the most immature neonates. These studies likewise have demonstrated that infants with VLBW are capable of responding to EPO with a reticulocytosis. Recent studies and a Cochrane Neonatal Systemic review suggest an association between exogenous EPO administration and retinopathy of prematurity.²  EPO with iron does not adversely affect growth or developmental outcomes, but the impact on the number of transfusions a premature infant receives ranges from nonexistent to small.
• At this time, no agreement regarding the safety, timing, dosing, route, or duration of therapy has been established. In short, the cost-benefit ratio for EPO has yet to be clearly established, and this medication is not universally accepted as a standard therapy for an infant with AOP.

Consultations

• Neonatology
• Pediatric hematology

Diet

• Provision of adequate amounts of vitamin E, vitamin B-12, folate, and iron are important to avoid exacerbating the expected decline in hemoglobin levels in the premature infant.

Medication

Growth factors

These agents are hormones that stimulate production of red cells from the erythroid tissues in the bone marrow.

Epoetin alfa (Epogen, Procrit)

Used to stimulate erythropoiesis and decrease the need for erythrocyte transfusions in high-risk preterm neonates. Stimulates division and differentiation of committed erythroid progenitor cells. Induces release of reticulocytes from bone marrow into blood stream.
Infants require supplemental iron. Some physicians also use vitamin E and folate.

Vitamins and minerals

These are organic substances required by the body in small amounts for various metabolic processes. They are used clinically for the prevention and treatment of specific deficiency states.

Ferrous sulfate (PO)/Iron dextran (IV)

Nutritionally essential inorganic substance. Mainstay treatment for treating patients with iron deficiency anemia.

Vitamin E (Aquasol E, Aquavit E)

Protects polyunsaturated fatty acids in membranes from attack by free radicals and protects RBCs against hemolysis. Available as PO liquid drops (15 IU/0.3 mL).

Folic acid (Folvite)

Water-soluble vitamin used in nucleic acid synthesis. Required for normal erythropoiesis. Important cofactor for enzymes used in production of RBCs

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