82: Anemia

Anemia developing during the neonatal period (0–28 days of life) in infants of >34 weeks' gestational age is indicated by a central venous hemoglobin <13 g/dL or a capillary hemoglobin <14.5 g/dL.

Anemia is the most common hematologic abnormality in the newborn. Specific incidence depends on the cause of the anemia.

1. Normal physiology. At birth, normal values for the central venous hemoglobin in infants of >34 weeks' gestational age are 14–20 g/dL, with an average value of 17 g/dL. Reticulocyte count in the cord blood of infants ranges from 3–7%. The average mean corpuscular volume of red blood cells (RBCs) is 107 fL. Premature infants have slightly lower hemoglobin and higher mean corpuscular volume and reticulocyte counts. In healthy term infants, hemoglobin values remain unchanged until the third week of life and then decline, reaching a nadir of 11 g/dL at 8–12 weeks. This is known as the “physiologic anemia of infancy.” In preterm infants, this decline is more profound, reaching a nadir of 7–9 g/dL at 4–8 weeks. This exaggerated physiologic anemia of prematurity is related to a combination of decreased RBC mass at birth, increased iatrogenic losses from laboratory blood sampling, shorter RBC life span, inadequate erythropoietin production, and rapid body growth. In the absence of clinical complications associated with prematurity, infants remain asymptomatic during this process.

2. Etiologies of anemia. Anemia in the newborn infant results from 1 of 3 processes: loss of RBCs, or hemorrhagic anemia, the most common cause; increased destruction of RBCs, or hemolytic anemia; or underproduction of RBCs, or hypoplastic anemia.

   1. Hemorrhagic anemia

      1. Antepartum period (1 in 1000 live births)

         1. Loss of placental integrity. Abruptio placentae, placenta previa, or traumatic amniocentesis (acute or chronic) may result in loss of placental integrity.

         2. Anomalies of the umbilical cord or placental vessels. Velamentous insertion of the umbilical cord occurs in 10% of twin gestations and almost all gestations with >3 fetuses. Communicating vessels (vasa praevia), umbilical cord hematoma (1 in 5500 deliveries), or entanglement of the cord by the fetus may also cause hemorrhagic anemia.

         3. Twin-twin transfusion. Observed only in monozygotic multiple births. Monozygotic (MZ) twin pregnancies account for ∼30% of spontaneously conceived twins. The occurrence of MZ twins is 0.4–0.45% of nonstimulated in vivo conceptions. The incidence of monochorionic twins is rising, owing to the increase in the use of assisted reproductive technology (ART). The use of ART has been associated with a 2- to 12-fold increase in the conception of MZ twins. In the presence of a monochorionic placenta, 13–33% of twin pregnancies are associated with twin-twin transfusion. The difference in hemoglobin concentration between twins is >5 g/dL. The anemic donor twin may develop congestive heart disease, whereas the recipient plethoric twin may manifest signs of the hyperviscosity syndrome. In utero laser photocoagulation, which interrupts the vascular connections on the chorionic plate, has improved the low survival rate for twin-twin transfusion diagnosed before 26 weeks' gestation.

      2. Intrapartum period

         1. Fetomaternal hemorrhage. Fetomaternal hemorrhage is a common event during pregnancy, demonstrable in ∼75% of gestations. The risk is increased with preeclampsia, with the need for instrumentation, and with cesarean delivery. In ∼8% of pregnancies, the volume of the hemorrhage is >10 mL. Clinically significant fetomaternal hemorrhage has traditionally been set at a cutoff of 30 mL. At this cutoff, the incidence of fetomaternal hemorrhage has been estimated to be 3 per 1000 births. With bleeds >80 mL/kg, two-thirds of the fetuses may die before delivery. The severity of the fetomaternal hemorrhage is related to the size of the bleed in relation to the overall fetal blood volume, as well as the rate at which this blood is lost, and whether the event is acute or chronic.

         2. Cesarean delivery. In elective cesarean deliveries, there is a 3% incidence of anemia. The incidence is increased in emergency cesarean deliveries.

         3. Traumatic rupture of the umbilical cord. Rupture may occur if delivery is uncontrolled or unattended.

         4. Failure of placental transfusion. Failure is usually caused by umbilical cord occlusion (eg, a nuchal cord or an entangled or prolapsed cord) during vaginal delivery. Blood loss may be 25–30 mL in the newborn.

         5. Obstetric trauma. During a difficult vaginal delivery, occult visceral or intracranial hemorrhage may occur. It may not be apparent at birth. Difficult deliveries are more common with large for gestational age infants, breech presentation, or difficult extraction.

      3. Neonatal period

         1. Enclosed hemorrhage. Hemorrhage severe enough to cause neonatal anemia suggests obstetric trauma, severe perinatal distress, or a defect in hemostasis. See Figure 6–1.

            • (a) Caput succedaneum is relatively common and may result in benign hemorrhage.

            • (b) Cephalhematoma is found in up to 2.5% of births. It is associated with vacuum extraction and primiparity (5% risk of associated linear nondepressed skull fracture).

            • (c) Subgaleal (subaponeurotic) hemorrhage is a rare but potentially lethal medical emergency caused by rupture of the emissary veins, which are connections between the dural sinuses and the scalp veins. Blood accumulates between the epicranial aponeurosis of the scalp and the periosteum. This potential space extends forward to the orbital margins, backward to the nuchal ridge, and laterally to the temporal fascia. In term infants, this subaponeurotic space may hold as much as 260 mL of blood. Subgaleal hemorrhage is most often associated with vacuum extraction and forceps delivery, but it may also occur spontaneously from an associated coagulopathy.

            • (d) Intracranial hemorrhage may occur in the subdural, subarachnoid, or subependymal space.

            • (e) Visceral parenchymal hemorrhage is uncommon. It is usually the result of obstetric trauma (eg, difficult breech extraction) to an internal organ, most commonly the liver but also the spleen, kidneys, or adrenal glands.

         2. Defects in hemostasis. Defects in hemostasis may be congenital, but more commonly hemorrhage occurs secondary to consumption coagulopathy, which may be caused by the following:

            • (a) Congenital coagulation factor deficiency

            • (b) Consumption coagulopathy

              • (i) Disseminated congenital or viral infection

              • (ii) Bacterial sepsis

              • (iii) Intravascular embolism of thromboplastin (as a result of a dead twin, maternal toxemia, necrotizing enterocolitis, or others)

            • (c) Deficiency of vitamin K–dependent coagulation factors (factors II, VII, IX, and X)

              • (i) Failure to administer vitamin K at birth usually results in a bleeding diathesis at 3–4 days of age.

              • (ii) Use of antibiotics may interfere with the production of vitamin K by normal gastrointestinal flora.

              • (iii) Maternal ingestion of anticonvulsant (carbamazepine, phenytoin, and barbiturates but not valproic acid), antituberculosis agent (isoniazid, rifampicin), and vitamin K antagonists.

            • Thrombocytopenia. See Chapter 139.

              • (i) Immune thrombocytopenia may be isoimmune or autoimmune.

              • (ii) Congenital thrombocytopenia with absent radii is a syndrome frequently associated with hemorrhagic anemia in the newborn.

              • (iii) Iatrogenic blood loss. Anemia may occur if blood loss resulting from repeated venipuncture is not replaced routinely. Symptoms may develop if a loss of >20% occurs within a 48-hour period.

   2. Hemolytic anemia

      1. Immune hemolysis

         1. Isoimmune hemolytic anemia. Caused mostly by Rh incompatibility.

         2. Autoimmune hemolytic anemia.

      2. Nonimmune hemolysis

         1. Bacterial sepsis may cause primary microangiopathic hemolysis.

         2. Congenital TORCH (toxoplasmosis, other, rubella, cytomegalovirus, and herpes simplex virus) infections (see Chapter 141).

      3. Congenital erythrocyte defect

         1. Metabolic enzyme deficiency

            • (a) Glucose-6-phosphate dehydrogenase (G6PD) deficiency

            • (b) Pyruvate kinase deficiency

         2. Thalassemia. Hemolytic anemia secondary to thalassemia is invariably associated with homozygous α-thalassemia and presents at birth. The disorders in β-thalassemia become apparent only after 2–3 months of age.

         3. Hemoglobinopathy. May be characterized as unstable hemoglobins or congenital Heinz body anemia.

         4. Membrane defects. Usually autosomal dominant.

            • (a) Hereditary spherocytosis (1 in 5000 neonates) commonly presents with jaundice and less often with anemia.

            • (b) Hereditary elliptocytosis (1 in 2500 neonates) rarely presents in the newborn infant.

      4. Systemic diseases

         1. Galactosemia

         2. Osteopetrosis

      5. Nutritional deficiency. Vitamin E deficiency occurs with chronic malabsorption but usually does not present until after the neonatal period.

   3. Hypoplastic anemia

      1. Congenital disease

         1. Diamond-Blackfan syndrome (congenital hypoplastic anemia)

         2. Atransferrinemia

         3. Congenital leukemia

         4. Sideroblastic anemia

      2. Acquired disease

         1. Infection. Rubella and syphilis are the most common causes.

         2. Aplastic crisis.

         3. Aplastic anemia.

Prematurity, certain race and ethnic groups, and hereditary blood disorders (see Section III).

1. Symptoms and signs. The 4 major forms of neonatal anemia may be demonstrated by determination of the following factors: age at presentation of anemia, associated clinical features at presentation, hemodynamic status of the infant, and presence or absence of compensatory reticulocytosis.

   1. Hemorrhagic anemia. Often dramatic in clinical presentation when acute but may be more subtle when chronic. Both forms have significant rates of perinatal morbidity and mortality if they remain unrecognized. Neither form has significant elevation of bilirubin levels or hepatosplenomegaly.

      1. Acute hemorrhagic anemia. Presents at birth or with internal hemorrhage after 24 hours. There is pallor not associated with jaundice and often without cyanosis (<5 g of deoxyhemoglobin) and unrelieved by supplemental oxygen. Tachypnea or gasping respirations are present. Vascular instability ranges from decreased peripheral perfusion (a 10% loss of blood volume) to hypovolemic shock (20–25% loss of blood volume). There is also decreased central venous pressure and poor capillary refill. Normocytic or normochromic RBC indices are present, with reticulocytosis developing within 2–3 days of the hemorrhagic event.

      2. Chronic hemorrhagic anemia. Presents at birth with unexplained pallor, often without cyanosis (<5 g of deoxyhemoglobin), and unrelieved by supplemental oxygen. Minimal signs of respiratory distress are present. The central venous pressure is normal or increased. Microcytic or hypochromic RBC indices are present, with compensatory reticulocytosis. The liver is often enlarged because of compensatory extramedullary erythropoiesis. Hydrops fetalis or stillbirth may occur with failure of compensatory reticulocytosis or intravascular volume maintenance.

      3. Asphyxia pallida (severe neonatal asphyxia). Not associated with hemorrhagic anemia at presentation. This disorder must be distinguished clinically from acute hemorrhage because specific immediate therapy is needed for each disorder. Asphyxia pallida presents at birth with pallor and cyanosis, which improves with supplemental oxygen delivery, respiratory failure, bradycardia, and normal central venous pressure.

   2. Hemolytic anemia. Jaundice is often seen before diagnostic levels of hemoglobin are obtained, in part because of the compensatory reticulocytosis that is invariably present. The infant usually presents with pallor after 48 hours of age. However, severe Rh isoimmune disease or homozygous α-thalassemia presents at birth with severe anemia and, in many cases, hydrops fetalis. Unconjugated hyperbilirubinemia of >10–12 mg/dL, tachypnea, and hepatosplenomegaly may be seen with hemolytic anemia.

   3. Hypoplastic anemia. Uncommon. It is characterized by presentation after 48 hours of age, absence of jaundice, and reticulocytopenia.

   4. Other forms of anemia

      1. Anemia associated with twin-twin transfusion. If chronic hemorrhage is occurring, there is often a >20% difference in the birthweights of the 2 infants, with the donor being the smaller twin.

      2. Occult (internal) hemorrhage

         1. Intracranial hemorrhage. Signs include a bulging anterior fontanel and neurologic signs (eg, a change in consciousness, apnea, or seizures).

         2. Visceral hemorrhage. Most commonly, the liver has been injured. An abdominal mass or distention is seen.

         3. Pulmonary hemorrhage. Partial or total radiographic opacification of a hemithorax and bloody tracheal secretions are seen. (See Chapter 74.)

2. History

   1. Anemia at birth

      1. Hemorrhagic anemia. There may be a history of third-trimester vaginal bleeding or amniocentesis. Hemorrhagic anemia may be associated with multiple gestation, maternal chills or fever postpartum, and nonelective cesarean delivery.

      2. Hemolytic anemia. May be associated with intrauterine growth restriction (IUGR) and Rh-negative mothers.

   2. Anemia presenting after 24 hours of age is often associated with obstetric trauma, unattended delivery, precipitous delivery, perinatal fetal distress, or a low Apgar score.

   3. Anemia presenting with jaundice suggests hemolytic anemia. There may be evidence of drug ingestion late in the third trimester; IUGR; a family member with splenectomy, anemia, jaundice, or cholelithiasis; maternal autoimmune disease; or Mediterranean or Asian ethnic background.

1. Obligatory initial studies

   1. Hemoglobin

   2. RBC indices

      1. Microcytic or hypochromic RBC indices suggest fetomaternal or twin-twin hemorrhage or α-thalassemia (mean corpuscular volume <90 fL).

      2. Normocytic or normochromic RBC indices are suggestive of acute hemorrhage, systemic disease, intrinsic RBC defect, or hypoplastic anemia.

   3. Reticulocyte count (corrected). An elevated reticulocyte count is associated with antecedent hemorrhage or hemolytic anemia. A low count is seen with hypoplastic anemia. The following formula is used:

      

   4. Blood smear

      1. Spherocytes are associated with ABO isoimmune hemolysis or hereditary spherocytosis.

      2. Elliptocytes are seen in hereditary elliptocytosis.

      3. Pyknocytes may be seen in G6PD deficiency.

      4. Schistocytes or helmet cells are most often seen with consumption coagulopathy.

   5. Direct antiglobulin test (direct Coombs test). This test is positive in isoimmune or autoimmune hemolysis.

2. Other selected laboratory studies

   1. Isoimmune hemolysis. The blood type and Rh type should be determined and an eluate of neonatal cells prepared.

   2. Fetomaternal hemorrhage. The Kleihauer-Betke test should be performed. Using an acid elution technique, a maternal blood smear is stained with eosin. Fetal RBCs containing hemoglobin F resistant to acid elution stain darkly. Adult RBCs voided of their acid-sensitive hemoglobin A do not stain and appear as “ghost cells.” A 50-mL loss of fetal blood into the maternal circulation shows up as 1% fetal cells in the maternal circulation. ABO incompatibility between mother and infant results in an increased clearance rate of fetal cells from the maternal circulation, giving a falsely low result. Conversely, the Kleihauer-Betke test may overestimate the extent of the hemorrhage, with maternal conditions leading to the overproduction of maternal hemoglobin F such as hereditary sickle-cell anemia, and β-thalassemia trait. Immunofluorescence flow cytometry is an alternative diagnostic test that circumvents some of the problems associated with the Kleihauer-Betke screen. This technology quantifies the number of fetal cells present by measuring the fluorescence intensity of monoclonal antibodies binding to hemoglobin F or to other surface antigens (eg, carbonic anhydrase) differentially expressed in fetal compared with adult erythrocytes. The College of American Pathologists has published a tool, accessible online at www.cap.org, which allows users to plug in the percentage of fetal cells observed by Kleihauer-Betke test or flow cytometry and the maternal height and weight to calculate the fetomaternal hemorrhage volume.

   3. Congenital hypoplastic or aplastic anemia. Bone marrow aspiration is usually indicated.

   4. TORCH infection

      1. Skull and long-bone films

      2. IgM levels

      3. Acute or convalescent serology

      4. Urine culture for cytomegalovirus

   5. Consumption coagulopathy

      1. Prothrombin time (PT) and partial thromboplastin time (PTT)

      2. Platelet count

      3. Thrombin time or fibrinogen assay

      4. Factor V and factor VIII levels

      5. Fibrin split products (d-dimers)

   6. Occult hemorrhage

      1. Pathologic examination of the placenta

      2. Cranial or abdominal ultrasonography will help identify the site of bleeding

   7. Intrinsic RBC defect

      1. RBC enzyme studies

      2. Analysis of the globin chain ratio

      3. Studies of RBC membrane

Treatment of neonatal anemia may involve, individually or in combination, simple replacement transfusion, exchange transfusion, nutritional supplementation, or treatment of the underlying primary disorder.

1. Simple replacement transfusion

   1. Indications

      1. Acute hemorrhagic anemia.

      2. Ongoing deficit replacement.

      3. Maintenance of effective oxygen-carrying capacity. There are no universally accepted guidelines; however, those presented next are fairly representative of most common practice.

         1. Hematocrit <35% with severe cardiopulmonary disease (eg, intermittent positive-pressure ventilation with mean airway pressure >6 cm H₂O).

         2. Hematocrit <30%

            • (a) With mild to moderate cardiopulmonary disease (Fio₂ >35%, continuous positive airway pressure).

            • (b) Significant apnea (>9–12 hours, or requiring bag-and-mask ventilation).

            • (c) “Symptomatic anemia” weight gain <10 g/kg/d at full caloric intake and heart rate >180 beats/min persisting for 24 hours.

            • (d) If undergoing major surgery.

         3. Hematocrit <21%. Asymptomatic but with low reticulocyte count (<2%).

   2. Emergency transfusion at birth only. Use type O, Rh-negative packed RBCs.

      1. Adjust the hematocrit to 50%.

      2. If a medical emergency exists, blood that has not been cross-matched may be given; if time permits, blood may be cross-matched to the mother's blood.

      3. Alternative replacement fluids include normal saline, fresh-frozen plasma, and 5% albumin in saline. Timely infusion of packed RBCs or partial exchange transfusion should follow.

      4. Perform umbilical vein catheterization to a depth of 4–5 cm or until free blood flow is established (see Chapter 44).

      5. Draw initial blood samples for diagnostic studies. Obtain a complete blood count and differential, blood type and Rh type, direct Coombs test, and, if indicated, total bilirubin levels. In a medical emergency, transfusion may be started before the results of laboratory testing are known.

      6. Infuse 10–15 mL/kg of replacement fluid over 10–15 minutes if emergency measures are needed. Once the infant's status is stable, reassess the diagnostic studies, physical examination, and obstetric history.

      7. Calculate the RBC volume. Under controlled circumstances or if simple transfusion is indicated, calculate the volume of packed RBCs needed to achieve the desired increase in RBC mass (see Hct <30–35%). The volume of a single transfusion should not exceed 10–20 mL/kg.

2. Exchange transfusion

   1. Indications

      1. Chronic hemolytic anemia or hemorrhagic anemia with evidence of tissue hypoxia (poor perfusion, metabolic acidosis, oliguria)

      2. Severe isoimmune hemolytic anemia with circulating sensitized RBCs and isoantibody

      3. Consumption coagulopathy

   2. Technique. See Chapter 30 for the technique of exchange transfusion in neonates.

3. Nutritional replacement

   1. Iron. Iron replacement is useful in the following situations:

      1. Fetomaternal hemorrhage of significant volume.

      2. Chronic twin-twin transfusion (in the donor twin).

      3. Incremental external blood loss (if unreplaced).

      4. Preterm infant (<36 weeks' gestational age).

   2. Folate. Especially with serum levels <0.5 ng/mL.

      1. Premature infants weighing <1500 g or <34 weeks' gestational age.

      2. Chronic hemolytic anemias or conditions involving “stress erythropoiesis.”

      3. Infants receiving phenytoin (Dilantin).

   3. Vitamin E. Preterm infants of <34 weeks' gestational age, unless they are being breast-fed.

4. Prophylactic

   1. Recombinant human erythropoietin (r-HuEPO) (controversial). High doses of erythropoietin are capable of increasing neonatal erythropoiesis and have very little adverse side effect. It decreases the requirement for “late” transfusions (those required past the age of 2–3 weeks); it will not compensate for the anemia secondary to phlebotomy losses. Its use in the very low birthweight infant continues to be controversial because the severity of anemia in this group can be more effectively minimized by a restrictive policy for blood sampling and the use of micromethods in the laboratory. The need for transfusions is also reduced when a consistent “protocolized” approach for transfusions is available in the neonatal intensive care unit. It has been also argued that what needs to be avoided, more than the transfusion itself, is the exposure to multiple donors. The allocation of a single donor for each high-risk infant, for a 42-day period, is the most effective way to reach that former goal. Early and late strategies have been used for erythropoietin treatment. (See doses in Chapter 148.)

      1. Early. Starting on day 1 or 2, 1200–1400 U/kg/wk. r-HuEPO is added to the total parenteral nutrition solution, and 1 mg/kg/d of iron is added.

      2. Late. 500–700 U/kg/wk given 3–5 times per week subcutaneously. Supplemental oral iron needs to be provided at 3 mg/kg/d in 3 divided doses. The iron dose is increased to 6 mg/kg/d as soon as the infant is tolerating full enteral feeds.

   2. Nutritional supplementation

      1. Elemental iron. 1–2 mg/kg/d, beginning at 2 months of age and continuing through 1 year of age.

      2. Folic acid. 1–2 mg/wk for preterm infants; 50 mcg/d for term infants.

      3. Vitamin E. 25 IU/d until a corrected age of 4 months is reached.

5. Treatment of selected disorders

   1. Consumption coagulopathy

      1. Treat the underlying cause (eg, sepsis).

      2. Give blood replacement therapy. Perform exchange transfusion or give fresh-frozen plasma, 10 mL/kg every 12–14 hours. Platelet concentrate, 1 U, may be used as a substitute for plasma transfusion.

      3. Perform coagulation studies. Monitor the PTT, PT, and fibrinogen and d-dimers levels and the platelet count.

   2. Immune thrombocytopenia

      1. Isoimmune thrombocytopenia

         1. Consider performing cesarean delivery if the diagnosis has been confirmed and there is an older sibling with immune thrombocytopenia (75% risk of recurrence).

         2. Give maternal washed platelets when indicated for bleeding diathesis in an infant with a platelet count <20,000–30,000 μL. Exchange transfusion may be used as an alternative.

         3. Corticosteroid therapy and intravenous immune globulin are controversial.

      2. Autoimmune thrombocytopenia

         1. Cesarean delivery. Consider if the maternal platelet count is <100,000 μL or the fetal platelet count is <50,000 μL.

         2. Use of corticosteroids is controversial. Under the conditions just mentioned, consider giving corticosteroids to the mother several weeks before delivery. Transfusion of random donor platelets may be given when indicated.

Depends on the underlying cause, its severity, and how acutely the anemia develops.