Anemia of Prematurity

Definition And Physiology

• A postnatal fall in hemoglobin is expected physiologically in all neonates.
• In term infants, the hemoglobin nadir is reached between 8 and 12 weeks of age.
• In preterm infants, the hemoglobin nadir is reached earlier, between 4 and 6 weeks of postnatal age.
• The hemoglobin nadir in premature babies is lower, typically 7 to 8 g/dL.
• In utero, the fetal aortic oxygen saturation is low at 45 percent.
• This low oxygen saturation keeps erythropoietin levels high and red blood cell production rapid.
• After birth, oxygen saturation rises to 95 percent.
• This increase in tissue oxygen levels suppresses erythropoietin production.
• Preterm babies differ in many developmental aspects of erythropoiesis.
• Erythropoietin production happens mostly in the liver in preterm infants.
• The transition to erythropoietin production in the kidney happens closer to term gestation.
• The liver is less sensitive to hypoxia, leading to physiologically low erythropoietin levels.
• This lower erythropoietin level is associated with lower rates of erythropoiesis and lower reticulocyte counts.
• Red blood cell survival is decreased in preterm infants compared with term infants.
• A relatively rapid rate of growth in premature babies causes a consequent increase in total blood volume.

Role Of Iron

• Preterm babies are iron deficient at birth.
• They miss the significant part of iron transfer that normally happens in the last trimester of gestation.
• Placental pathology, like placental insufficiency, can cause a further decrease in iron transfer.
• Iron deficiency is not the cause of anemia of prematurity.
• Supplementation with iron will not change the nadir of the hemoglobin level or diminish its rate of reduction.
• Iron is preferentially used by red blood cells.
• Deficiency results in lower amounts of iron supplied to the developing brain.
• Iron is a critical nutrient for the fetal brain.
• Iron deficiency can result in permanent deviations in brain development that are not reversed by later correction.

Iatrogenic Blood Loss

• Excessive blood loss may result from blood sampling-associated losses.
• This is possibly the most common cause of anemia in the neonatal intensive care unit.
• Iatrogenic blood sampling losses in the neonatal intensive care unit are often not replaced.
• This lost red blood cell mass also accounts for significant iron losses.
• Studies have described blood volumes drawn for lab tests to be as high as 35 mL in very low birth weight babies.
• Many preterm infants have reduced red cell mass because of iatrogenic phlebotomy.

Clinical Presentation And Evaluation

• Asymptomatic, adequately growing preterm babies may be quite comfortable with hemoglobin levels as low as 6.5 to 7.0 g/dL.
• Premature infants may be considered for transfusion if they exhibit poor weight gain, apnea, tachypnea, or lethargy.
• Symptomatic anemia is defined by postnatal age, the need for respiratory support, and hemoglobin below specific thresholds.
• A heart rate greater than 180 beats per minute or a respiratory rate greater than 60 breaths per minute for 24 hours suggests symptomatic anemia.
• A doubling of the oxygen requirement in the previous 48 hours is a sign of symptomatic anemia.
• A serum lactate of 2.5 mEq/L or more indicates poor oxygen delivery.
• An acute metabolic acidosis with a pH less than 7.2 also suggests symptomatic anemia.
• Weight gain less than 10 g/kg/day over the previous four days despite adequate caloric intake indicates significant anemia.

Management Strategies

Iron Supplementation

• Iron supplementation in preterm infants is recommended by 2 to 4 weeks of age.
• The recommended dose is 2 to 4 mg/kg/day.
• Early iron supplementation ensures sufficient supplies for the developing brain.
• It allows the building of iron stores by replacing the red cell mass lost through sampling.
• Early supplementation lowers the risk of late iron deficiency anemia noted at 4 to 6 months of life.
• Very low birth weight infants should receive supplemental iron for the first 12 to 15 months of life.
• Serum ferritin can be monitored periodically starting from 1-month postnatal age to optimize iron therapy.
• If serum ferritin is greater than 300 µg/L, mostly following blood transfusions, iron may be stopped for a short period.
• Iron supplementation is not associated with a risk of sepsis or feed intolerance.
• A change in stool color to black must be communicated to parents.

Packed Red Blood Cell Transfusions

• The decision to treat anemia with packed red blood cell transfusions takes into consideration hemoglobin levels, gestation, postnatal age, and cardiorespiratory status.
• The absolute hemoglobin or hematocrit level itself is not an indication for transfusion.
• Restrictive transfusion thresholds significantly reduce unnecessary transfusions and associated risks.
• Well-designed clinical trials have concluded that restrictive thresholds are safe regarding acute and long-term outcomes.
• Overuse of packed red blood cells in babies with cardiorespiratory instability is common due to false expectations of improved oxygen delivery.

Transfusion Thresholds For Preterm Neonates

• The following table represents hemoglobin transfusion thresholds for preterm neonates less than 32 weeks of gestation.

Blood Product Specifications

• Whole blood is not recommended for transfusing neonates for anemia.
• Packed red blood cells are used for the correction of severe anemia.
• Leukocyte-depleted packed red blood cells are recommended in premature infants weighing less than 1200 grams.
• Leukocyte depletion substantially reduces the risk of exposure to foreign lymphocytes and cytomegalovirus.
• It also prevents non-hemolytic febrile transfusion reactions and transfusion-related acute lung injury.
• Irradiated packed red blood cells have fewer T-lymphocytes, reducing the risk of transfusion-associated graft versus host disease.
• Freshly irradiated red blood cells have an advantage in preterm infants due to better cerebral oxygenation.
• Irradiated blood must be used within 24 hours to avoid potassium accumulation.
• For stable preterm babies receiving top-up transfusions, standard issue blood can be used within 35 days of donation.
• Fresh blood less than 5 days old is only required for large-volume transfusions, cardiac surgery, or exchange transfusions.

Transfusion Dosing And Administration

• Small volume packed red blood cell transfusions are preferred in babies less than 32 weeks due to the reported risk of necrotizing enterocolitis.
• The standard dose is 10 to 15 mL/kg.
• Transfusions are initiated at slow rates of 2 mL/minute to watch for reactions.
• The recommended rate for transfusion is 5 mL/kg/hour.
• The transfusion may be completed over 2 to 3 hours in well babies.
• In preterm babies less than 29 weeks and weighing less than 1250 grams, the transfusion may be completed over 4 hours.
• There is no need to give a dose of diuretic before or after a transfusion unless indicated for pre-existing cardiac failure.

Prevention Strategies

Minimizing Blood Loss

• Preventing phlebotomy losses by utilization of microsampling techniques is crucial.
• Standard methods require at least 2000 µL, while microsampling can perform tests in less than 150 µL of blood.
• Unnecessary laboratory testing must be minimized.
• Blood may be collected from the placental end of the umbilical cord for initial lab tests and blood cultures to spare the infant's blood.

Delivery Room Interventions

• Delayed cord clamping lowers the incidence of anemia and iron deficiency in term and preterm babies.
• It increases the peak hematocrit and reduces the proportion of neonates needing blood transfusion.
• It should be attempted for a minimum time of 30 seconds to 180 seconds after delivery.
• Umbilical cord milking is comparable to delayed cord clamping in improving hemoglobin levels.
• Umbilical cord milking should be strictly avoided in infants born at 23 to 27 weeks of gestation due to an increased risk of severe intraventricular hemorrhage.

Decreasing Donor Exposure

• Satellite bags limit the number of donor exposures.
• These are small bags prepared by splitting the blood from a standard packed red blood cell bag.
• Reserving a fresh unit of packed red blood cells for a neonate at their first transfusion allows subsequent transfusions to utilize aliquots of that unit until it expires.

Pharmacological Prevention

• Recombinant human erythropoietin stimulates red blood cell production.
• It is associated with a decrease in the frequency and volume of red blood cell transfusions if initiated before 8 days of age in extreme premature infants.
• The benefits are limited if strict blood conservation strategies are already implemented.
• An increase in retinopathy of prematurity was reported in some studies.
• A multicentric study found no significant impact on mortality or severe neurodevelopmental impairment.
• Erythropoietin prophylaxis is not currently recommended for routine use.

Complications Of Transfusion

• Transfusion-associated necrotizing enterocolitis is observed in close temporal proximity to blood transfusions.
• Increased frequency has been associated with splanchnic ischemia during transfusions.
• The practice of withholding feeding around the time of transfusion is not supported by consistent evidence and cannot be uniformly recommended.
• Severe anemia prior to transfusion may actually be the primary risk factor for necrotizing enterocolitis.
• Transfusion-associated circulatory overload occurs in rapid and large-volume transfusions.
• Cytomegalovirus transmission remains a significant concern in preterm neonates.
• Transfusion-associated graft versus host disease is a fatal complication where transfused donor lymphocytes mount an immune response against the immunocompromised patient.
• Packed red blood cell transfusion is an independent risk factor for retinopathy of prematurity.
• This is possibly related to the adult hemoglobin in the packed red blood cells having a lower oxygen affinity and greater capacity to release oxygen.
• The numerous pro-inflammatory and anti-inflammatory mediators in stored red blood cells could play a role in the pathophysiology of bronchopulmonary dysplasia.