Hematologic Conditions

Hematologic concerns can be present in both term and preterm infants as a result of prenatal and postnatal risk factors. Interpreting hematologic results is different in neonates than in older children because of changing physiology.

Anemia of Prematurity

Both term and preterm infants have a physiologic nadir in their hemoglobin concentration. For term infants, the nadir typically occurs between 6 and 12 weeks of age; for preterm infants, the timeline is sooner, and the nadir is more significant. Erythropoietin (EPO) is a primary regulator of erythropoiesis, and its natural downregulation with increased oxygen delivery (both increased blood oxygen content and increased tissue oxygen delivery) contributes to this nadir, although there is also an effect from phlebotomy and low iron stores, particularly in preterm infants who already have lower circulating blood volumes. Therefore, periodic screening of hemoglobin or hematocrit values is important for all infants in the NICU.

Transfusion Guidelines

Each NICU has transfusion guidelines for the unit to follow to ensure that infants maintain adequate cell lines and to limit any negative effects from transfusions.

Packed Red-Cell Transfusions

Infants with anemia can present with tachycardia, tachypnea, poor weight gain, or a combination of apnea, bradycardia, and oxygen desaturation. In a recent multicenter trial (the TOP trial) conducted among extremely-low-birth-weight infants, a higher hemoglobin transfusion threshold, as defined in the table below, did not improve survival without neurodevelopmental impairment. However, these thresholds may differ in infants that are undergoing surgical management or are otherwise critically ill.

Platelet Transfusions

There are many risk factors for the development of thrombocytopenia in neonates, including postnatal infections and being born to a mother with preeclampsia. Prophylactic platelet transfusions are administered to infants to reduce the risk of major bleeding. In a recent clinical trial (the PlaNet-2 trial) that evaluated platelet-count transfusion thresholds of 50,000 versus 25,000 per cubic millimeter among infants with severe thrombocytopenia, the higher threshold was associated with a significantly higher rate of death or major bleeding than the lower threshold.

Hyperbilirubinemia

Hyperbilirubinemia in the neonate is of concern because infants are at risk of developing bilirubin-induced neurologic dysfunction (BIND) secondary to bilirubin crossing the blood-brain barrier. As a result, all infants should be screened for hyperbilirubinemia during hospitalization to prevent bilirubin-induced encephalopathy and kernicterus.

Infants at all gestational ages are at risk for an elevated bilirubin level after birth because of the immaturity of the uridine diphosphate glucuronyltransferase (UDPGT) enzyme in the liver. Relative to older children, infants also have a higher erythrocyte count with a greater degree of heme breakdown that leads to an increased bilirubin load. Infants with blood-type incompatibility with the birthing person are at increased risk for significant hyperbilirubinemia due to hemolysis. In addition, premature infants are at elevated risk for bilirubin encephalopathy and kernicterus due to a more permeable blood-brain barrier.

Risk Factors

The most common risk factors for hyperbilirubinemia include exclusive breastfeeding, gestational age of <38 weeks, history of hyperbilirubinemia in a sibling, and jaundice appreciated in the patient before discharge. Other risk factors include bruising from delivery (cephalohematoma or subgaleal hemorrhage), polycythemia, ABO-blood-type incompatibility, and other hemolytic disorders.

Polycythemia can contribute to hyperbilirubinemia because of increased erythrocyte load. Polycythemia in a term newborn is defined as a hematocrit >65% in a venous sample. Risk factors for polycythemia include maternal diabetes, trisomy 21, small size for gestational age, placental insufficiency, delayed cord clamping, and cyanotic cardiac lesions. Complications of polycythemia other than hyperbilirubinemia include hyperviscosity leading to respiratory distress (tachypnea), thrombosis, and hypoglycemia. Management of polycythemia can include administration of intravenous (IV) fluids or a partial exchange transfusion. Certain medications (e.g., ceftriaxone) displace bilirubin from the albumin-bilirubin complex and should be used conservatively in neonates.

Types of Hyperbilirubinemia

The two main types of hyperbilirubinemia are based on the component of the serum bilirubin that is elevated: indirect (unconjugated bilirubin) or direct (conjugated bilirubin).

The following are causes of indirect hyperbilirubinemia:

• breastfeeding jaundice

• breast milk jaundice

• ABO incompatibility

• Rh incompatibility

• hemolysis due to other diseases

Breastfeeding jaundice is due to the low supply of maternal milk during the first 3 to 5 days of life and occurs in conjunction with physiologic hyperbilirubinemia. Management of breastfeeding jaundice includes monitoring the infant, encouraging frequent feeding, and using phototherapy as needed based on serum bilirubin levels. Once the maternal breast milk supply increases, infants will excrete more bilirubin in the stool.

Breast milk jaundice occurs after 7 days of life in exclusively breastfed infants and can last as long as one month. It is thought to be caused by a substance in maternal milk that prevents certain proteins in the infant’s liver from breaking down bilirubin. Temporary interruption of breastfeeding may be necessary, although breast milk jaundice typically resolves on its own.

Hemolysis due to ABO incompatibility or Rh isoimmunization can also contribute to hyperbilirubinemia. Other causes of hemolysis-induced hyperbilirubinemia include glucose-6-phosphate dehydrogenase deficiency (G6PD), hereditary spherocytosis or elliptocytosis (erythrocyte membrane defects), hemoglobinopathies (e.g., thalassemia syndromes), acquired infection, disseminated intravascular coagulation (DIC), and vitamin E deficiency.

Direct hyperbilirubinemia is defined as elevation of the conjugated portion of bilirubin concentration to >20% of total bilirubin. Causes of indirect hyperbilirubinemia include:

• structural anomalies (e.g., biliary atresia or choledochal cysts)

• genetic diseases (e.g., galactosemia or Alagille syndrome)

• intestinal failure-associated liver disease (due to prolonged parenteral nutrition administration and decreased enteral feeding)

Screening

Maternal screening: All mothers should have their blood typed during pregnancy. If a mother is blood type O or Rh-negative, the infant should also have their blood typed after birth to determine risk for incompatibility. The most commonly encountered maternal antibody is the Rh antibody (D antigen). Rh-negative blood type in a mother puts the infant at risk for Rh sensitization and hemolytic disease. In this situation, the mother will receive RhoGAM (an IgG antibody against Rh) at 28 weeks’ gestation. Other antibodies (including Kell and Duffy) can lead to hemolysis but at lower rates.

Hemolytic disease can also occur from ABO incompatibility between mother and infant. To determine the risk for hemolysis in infants, direct antiglobulin testing (DAT) is performed on infants born to mothers with blood type O (equivalent to the Coombs test). DAT-positive infants are at increased risk for hemolysis.

Infant screening: All infants are screened for elevated bilirubin prior to discharge from the hospital. This can be done with a transcutaneous or serum bilirubin. The transcutaneous measurement is only a screen and determines the need for further serum testing.

Management

In infants >35 weeks' gestation, once the risk for developing clinically significant hyperbilirubinemia has been determined from universal screening prior to hospital discharge, total serum bilirubin level by age in hours should be plotted on the Bhutani nomogram or BiliTool (based on the Bhutani nomogram) to determine need for phototherapy. The need for phototherapy can also be assessed by rate of rise over time. If the bilirubin rate increases >0.2 mg/dL per hour, phototherapy should be considered.

Premature infants (<35 weeks’ gestation) are at risk for adverse effects of bilirubin toxicity at lower thresholds than term infants because of their immature blood-brain barrier. More immature enzymes in the liver and poor gut motility also lead to reduced excretion of bilirubin and overall higher bilirubin levels. Phototherapy thresholds are therefore lower for premature infants than term infants. One resource for phototherapy thresholds in premature infants over 48 hours of age is Stanford’s Premie BiliRecs tool.

Exchange Transfusion

Exchange transfusions are now performed infrequently in the NICU. There are two types of exchange transfusions in the NICU, double and partial volume exchange, each with its own indication and procedure. For both types of exchange transfusion, the first step is obtaining central access.

Double-Volume Exchange

Double-volume exchange transfusions involve replacing the infant’s blood volume twice to remove toxins or antibodies from the infant’s systemic circulation. The most common indication for a double-volume exchange transfusion is significant hyperbilirubinemia above the exchange transfusion threshold. This procedure is done slowly to maintain a constant blood volume.

Partial-Volume Exchange

Partial-volume exchange transfusions aim to keep the infant’s total blood volume the same while reducing or increasing the infant’s hematocrit. The clinical indications for this type of transfusion include significant polycythemia or clinically significant anemia with normal circulating blood volume. An exchange with a blood transfusion is used to raise the infant’s HCT, and normal saline is used to lower the infant’s HCT. A formula is used to calculate the volume necessary.