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(See also Approach to the Patient With Anemia.)

Anemia is Hb or Hct > 2 standard deviations below mean for age. Both Hb and Hct change rapidly as a neonate matures, so lower limits of normal also change. Variables such as gestational age (see Table 1: Perinatal Hematologic Disorders: Age-Specific Values for Hemoglobin and Hematocrit), sampling site (capillary vs vein), and position of the neonate relative to the placenta before cord clamping (lower position causes blood to transfer in to the neonate; higher position causes blood to transfer out of the neonate) also affect test results.

Table 1
Age-Specific Values for Hemoglobin and Hematocrit AGE Hb (g/dL) Hct (%) 28 wk gestation 14.5 45 32 wk gestation 15 47 Term 16.5 51 1–3 days 18.5 56 2 wk 16.6 53

Etiology

Anemia in neonates may be physiologic, or it may be caused by blood loss, decreased RBC production, or increased RBC destruction (hemolysis).

Physiologic anemia: Normal physiologic processes often cause normocytic-normochromic anemia in term and preterm infants. Physiologic anemias do not generally require extensive evaluation or treatment.

In term infants, the increase in oxygenation that occurs with normal breathing after birth causes an abrupt rise in tissue O₂ level, resulting in negative feedback on erythropoietin production and erythropoiesis. This reduction in erythropoiesis, as well as the shorter lifespan (60 to 70 days vs 120 days in adults) of neonatal RBCs, causes Hb concentration to fall over the 1st 2 to 3 mo of life, usually no lower than 9.4 g/dL. Hb remains stable over the next several weeks, and then slowly rises in the 4th to 6th month secondary to renewed erythropoietin stimulation.

The same mechanism causes anemia in preterm infants during the 1st 4 to 12 wk, but lower erythropoietin production, shorter RBC life span (35 to 50 days), and more frequent phlebotomy contribute to a lower Hb nadir (8 to 10 g/dL). Infants < 32 wk gestation are most affected.

Blood loss: Anemia may develop because of prenatal, perinatal (at delivery), or postpartum hemorrhage. In neonates, blood volume is low (eg, preterm, 90 to 150 mL/kg; term, 78 to 86 mL/kg); therefore, acute loss of as little as 15 to 20 mL of blood may result in anemia. An infant with chronic blood loss can compensate physiologically and is typically more clinically stable than an infant with acute blood loss.

Prenatal hemorrhage may be caused by fetal-to-maternal hemorrhage, twin-to-twin transfusion, cord malformations, placental abnormalities, and diagnostic procedures. Fetal-to-maternal hemorrhage occurs spontaneously or as a result of maternal trauma, amniocentesis, external cephalic version, or placental tumor. It affects about 50% of pregnancies, although in most cases the volume of blood lost is extremely small (about 2 mL); “massive” blood loss, defined as > 30 mL, occurs in 3/1000 pregnancies. Twin-to-twin transfusion is the unequal sharing of blood supply between twins that affects 13 to 33% of monozygotic, monochorionic twin pregnancies. With significant blood transfer, the donor twin may become very anemic and develop heart failure, while the recipient may become polycythemic and develop hyperviscosity syndrome (see Perinatal Hematologic Disorders: Perinatal Polycythemia and Hyperviscosity Syndrome). Cord malformations include velamentous insertion of the umbilical cord, vasa previa, or abdominal or placental insertion; mechanism of hemorrhage is by cord vessel shearing or rupture. The 2 important placental abnormalities causing hemorrhage are placenta previa and abruptio placentae. Diagnostic procedures causing hemorrhage include amniocentesis, chorionic villus sampling, and umbilical cord blood sampling.

Perinatal hemorrhage may be caused by precipitous delivery (ie, rapid, spontaneous delivery < 3 h after onset of labor, which causes hemorrhage due to umbilical cord tearing) and obstetrical accidents such as incision of the placenta during cesarean section. Cephalhematomas from procedures such as vacuum or forceps delivery are usually relatively harmless, but subgaleal bleeds can extend into soft tissue, sequestering sufficient blood volumes to result in anemia, hypotension, shock, and death. Far less often, rupture of the liver, spleen, or adrenal gland during delivery may lead to internal bleeding. Intraventricular hemorrhage in preterm infants (see Perinatal Problems: Intracranial Hemorrhage) as well as subarachnoid and subdural bleeding also can result in a significantly lowered Hct.

Hemorrhagic disease of the newborn (see Vitamin Deficiency, Dependency, and Toxicity: Vitamin K Deficiency) is hemorrhage within a few days of a normal delivery caused by transient physiologic deficiency in vitamin K–dependent coagulation factors. Other possible causes of hemorrhage in the first few days of life are other coagulopathies (eg, hemophilia), disseminated intravascular coagulation from sepsis, vascular malformations, or prenatal maternal use of vitamin K antagonists (eg, phenytoin Some Trade Names
DILANTIN
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, warfarin Some Trade Names
COUMADIN
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, isoniazid Some Trade Names
INH
NYDRAZID
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).

Decreased RBC production: Defects in RBC production may be congenital or acquired.

Congenital defects are extremely rare, but Diamond-Blackfan and Fanconi's anemia are the most common.

Diamond-Blackfan anemia is characterized by lack of RBC precursors in bone marrow, macrocytic RBCs, lack of reticulocytes in peripheral blood, and lack of involvement of other blood cell lineages. It is often part of a syndrome of congenital anomalies including microcephaly, cleft palate, eye anomalies, thumb deformities, and web neck. Up to 25% of affected infants are anemic at birth, and low birth weight occurs in about 10%. It is thought to be caused by defective stem cell differentiation.

Fanconi's anemia is an autosomal recessive disorder of bone marrow progenitor cells that causes macrocytosis and reticulocytopenia with progressive failure of all hematopoietic cell lines. It is usually diagnosed after the neonatal period. The cause is a genetic defect that prevents cells from repairing damaged DNA or removing toxic free radicals that damage cells.

Other congenital anemias include Pearson's syndrome, a rare, multisystem disease involving mitochondrial defects that cause refractory sideroblastic anemia, pancytopenia, and variable hepatic, renal, and pancreatic insufficiency or failure; and congenital dyserythropoietic anemia, in which chronic anemia (typically macrocytic) results from ineffective or abnormal RBC production, and hemolysis caused by RBC abnormalities.

Acquired defects are those that occur after birth. The most common causes are infections (eg, malaria, rubella, syphilis, HIV, cytomegalovirus, adenovirus, bacterial sepsis) that impair RBC production in the bone marrow, and nutritional deficiency. Congenital parvovirus B19 infection may result in the absence of RBC production. Nutritional deficiencies of iron, copper, and folate and vitamins E and B₁₂ may cause anemia in the early months of life but not usually at birth. The incidence of iron deficiency, the most common nutritional deficiency, is higher in less developed countries where it results from dietary insufficiency and exclusive and prolonged breastfeeding. Iron deficiency is common in neonates whose mothers have an iron deficit and in premature infants whose formula is not supplemented with iron; premature infants deplete iron stores by 10 to 14 wk if not supplemented.

Hemolysis: Hemolysis (see also Anemias Caused by Hemolysis) may be immune-mediated or caused by RBC membrane disorders, enzyme deficiencies, hemoglobinopathies, or infection. All cause hyperbilirubinemia, which may cause jaundice and kernicterus (see Metabolic, Electrolyte, and Toxic Disorders in Neonates: Kernicterus).

Immune-mediated hemolysis may occur when fetal RBCs with surface antigens (most commonly Rh and ABO blood antigens but also Kell, Duffy, and other minor group antigens) that differ from maternal RBC antigens enter the maternal circulation and stimulate production of IgG antibody directed against fetal RBCs. The most common scenario is that an Rh (D antigen)-negative mother becomes sensitized to the D antigen during her 1st pregnancy with an Rh-positive fetus; a 2nd Rh-positive pregnancy may then prompt an IgG response that may result in fetal and neonatal hemolysis (see Abnormalities of Pregnancy: Erythroblastosis Fetalis). Intrauterine hemolysis may be severe enough to cause hydrops or death; postpartum, there may be significant anemia and hyperbilirubinemia with ongoing hemolysis secondary to persistent maternal IgG (half-life about 28 days). With widespread prophylactic use of anti-Rh D to prevent sensitization (see Abnormalities of Pregnancy: Prevention), < 0.11% of pregnancies in Rh-negative women are affected. ABO incompatibility may cause hemolysis by a similar mechanism but rarely results in severe hemolysis requiring treatment; the immunoglobulin involved is predominantly IgM, which is incapable of crossing the placenta. Hemolysis from ABO incompatibility sometimes occurs in a 1st pregnancy if the mother has been previously sensitized by antigens in foods or bacteria.

RBC membrane disorders alter RBC shape and result in premature removal of RBCs from the circulation. The most common disorders are hereditary spherocytosis and hereditary elliptocytosis (see Anemias Caused by Hemolysis: Hereditary Spherocytosis and Hereditary Elliptocytosis).

Deficiencies of G6PD (see Anemias Caused by Hemolysis: Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency) and pyruvate kinase (see Anemias Caused by Hemolysis: Embden-Meyerhof Pathway Defects) are the most common enzyme disorders causing hemolysis.

Hemoglobinopathies are caused by deficiencies and structural abnormalities of globin chains. At birth, 55 to 90% of the neonate's hemoglobin is composed of 2 alpha and 2 gamma globin chains (fetal hemoglobin or Hb F [α ² γ ²]). After birth, γ-chain production decreases (to < 2% by 2 to 4 yr of age) and β-chain production rises until adult hemoglobin (Hgb A [α ² β ²]) becomes predominant. α-Thalassemia (see Anemias Caused by Hemolysis: Etiology and Pathophysiology) is a genetically inherited disorder of depressed α globin chain production and is the most common hemoglobinopathy causing anemia in the neonatal period. β-Thalassemia (see Anemias Caused by Hemolysis: Etiology and Pathophysiology) is an inherited decrease in β-chain production. Because β globin is naturally low at birth, β-thalassemia and structural abnormalities of the β globin chain (Hb S [sickle cell disease], Hb C) are rarely apparent at birth and symptoms do not appear until fetal Hb levels have fallen to sufficiently low levels at 3 to 4 mo.

Intrauterine infections by certain bacteria, viruses, fungi, and protozoa (most notably toxoplasmosis and malaria) also may trigger hemolytic anemia. In malaria, the Plasmodium parasite invades and ultimately ruptures the RBC. Immune-mediated destruction of parasitized RBCs and excess removal of nonparasitized cells occur. Associated bone marrow dyserythropoiesis results in inadequate compensatory erythropoiesis. Intravascular hemolysis, extravascular phagocytosis, and dyserythropoiesis can lead to anemia.

Symptoms and Signs

Symptoms and signs are similar regardless of the cause but vary with severity and rate of onset of the anemia. Neonates are generally pale and, if anemia is severe, have tachypnea, tachycardia, and sometimes a flow murmur; hypotension is present with acute blood loss. Jaundice may be present with hemolysis.

Evaluation

History: History should focus on maternal factors (eg, bleeding diatheses, hereditary RBC disorders, nutritional deficiencies, drugs), family history of hereditable disorders that cause neonatal anemia, and obstetric factors (eg, infections, vaginal bleeding, obstetrical interventions, mode of delivery, blood loss, treatment and appearance of the cord, placental pathology, fetal distress, number of fetuses). Nonspecific maternal factors may provide additional clues; splenectomy would indicate a possible history of hemolysis or autoimmune anemia, and cholecystectomy might indicate past hemolysis (producing excess bile and hence gallstones). Important neonatal factors include gestational age at delivery, age at presentation, sex, race, and ethnicity.

Physical examination: Tachycardia and hypotension suggest acute, significant blood loss. Jaundice suggests hemolysis, either systemic (from ABO incompatibility or G6PD deficiency) or localized (from breakdown of sequestered blood in cephalhematomas). Hepatosplenomegaly suggests either hemolysis or heart failure. Hematomas, ecchymoses, or petechiae suggest bleeding diathesis; congenital anomalies may suggest a bone marrow failure syndrome.

Testing: Anemia may be suspected prenatally if ultrasound shows hydrops fetalis, which is abnormal, excessive fluid in 2 or more body compartments (eg, pleura, peritoneum, pericardium); cardiac, hepatic, and splenic enlargement may be present.

After birth, if anemia is suspected, reticulocytes should be measured and the peripheral smear examined. The percentage of reticulocytes increases in anemia caused by blood loss or hemolysis, reflecting an appropriate bone marrow response; reticulocyte count is low when anemia is caused by acquired or congenital bone marrow dysfunction.

Whenever the reticulocyte count is elevated or normal, a direct antiglobulin test (DAT, or Coombs' test) should be obtained. If the DAT is positive, anemia is likely secondary to Rh, ABO, or other blood group incompatibility. If the DAT is negative, the RBC mean corpuscular volume (MCV) may prove helpful; a significantly low MCV suggests α-thalassemia or chronic intrauterine blood loss. With a normal or high MCV, peripheral blood smear may demonstrate abnormal RBC morphology compatible with a membrane disorder, microangiopathy, disseminated intravascular coagulation (DIC), or hemoglobinopathy. If the smear is normal, blood loss, enzyme deficiency, or infection should be considered and appropriate work-up should ensue.

Fetal-to-maternal hemorrhage can be diagnosed by testing for fetal RBCs in maternal blood. The Kleihauer-Betke acid elution technique is the most frequently used test, but other tests include fluorescent antibody techniques and differential or mixed agglutination testing. In the Kleihauer-Betke technique, citric acid-phosphate buffer of pH 3.5 elutes hemoglobin from adult but not fetal RBCs; thus fetal RBCs stain with eosin and are visible on microscopy, whereas adult RBCs appear as red cell ghosts.

When the reticulocyte percentage is depressed, the infant should be evaluated for causes of bone marrow suppression with titers for viral infection (rubella, syphilis, HIV, cytomegalovirus, adenovirus), folate and vitamin B₁₂ levels, and iron and copper levels.

Treatment

Need for treatment varies with degree of anemia and associated medical conditions; otherwise healthy term and preterm infants with mild anemia generally do not require treatment. Treatment is directed at the underlying diagnosis. Some patients require transfusion or exchange transfusion of packed RBCs.

Transfusion: Transfusion is indicated to treat severe anemia. Guidelines for when to transfuse vary, but one accepted set is:

• Hb ≤ 12 g/dL (Hct ≤ 36%) in the 1st 24 h of life
• ≥ 10% decrease in Hb in 1 wk
• ≥ 10% acute blood loss
• Hb ≤ 12 g/dL in a neonate requiring intensive care
• Hb ≤ 11 g/dL in a neonate with chronic O₂ dependency
• Hb ≤ 7 g/dL in a stable infant with late (ie, 4 to 6 wk) anemia

Before the 1st transfusion, if not already done, maternal and fetal blood should be screened for ABO and Rh types and the presence of atypical RBC antibodies, and a DAT should be performed on the infant's RBCs.

Blood for transfusion should be the same as or compatible with the neonate's ABO and Rh group and with any ABO or RBC antibody present in maternal or neonatal serum. Neonates produce RBC antibodies only rarely, so in cases where the need for transfusion persists, repeat antibody screening is usually not necessary until 4 mo of age.

Packed RBCs used for transfusion should be filtered (leukocyte depleted), irradiated, and given in aliquots of 5 to 15 mL/kg derived from a single donation; sequential transfusions from the same unit of blood minimize recipient exposure and transfusion complications.

Exchange transfusion: Exchange transfusion, in which blood from the neonate is removed in aliquots in sequence with packed RBC transfusion, is indicated for hemolytic anemia and some cases of severe anemia with heart failure. It decreases plasma antibody titers and bilirubin levels (when phototherapy fails) and minimizes fluid overload. Serious adverse events (eg, shock, pulmonary edema, or both caused by shifts in fluid balance) are common, so the procedure should be performed by experienced staff. Guidelines for when to begin exchange transfusion differ and are not evidence based.

Other treatments: Recombinant human erythropoietin is not routinely recommended, in part because it has not been shown to reduce transfusion requirements in the 1st 2 wk of life.

Iron administration is restricted to cases of repetitive blood loss (eg, hemorrhagic diathesis, GI bleeding, frequent phlebotomy). Oral iron supplements are preferred; parenteral iron sometimes causes anaphylaxis and should be pursued under guidance of a hematologist.

Treatment of more unusual causes of anemia is disorder specific (eg, corticosteroids in Diamond-Blackfan anemia, vitamin B₁₂ for B₁₂ deficiency).

Last full review/revision November 2005

Content last modified November 2005