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(See also Approach to the Patient With Anemia.)
Anemia is Hb or Hct > 2 standard deviations below the mean for age. Both Hb and Hct change rapidly as a neonate matures, so lower limits of normal also change (see Table 1: Perinatal Hematologic Disorders: Age-Specific Values for Hemoglobin and Hematocrit ). Variables such as gestational age, 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.
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Table 1
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PrintOpen table  |
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| Age-Specific Values for Hemoglobin and Hematocrit |
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Age
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Hb (g/dL)
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Hct (%)
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28 wk gestation
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14.5
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45
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32 wk gestation
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15
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47
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Term
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16.5
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51
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1–3 days
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18.5
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56
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2 wk
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16.6
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53
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Etiology
Causes of anemia in neonates include
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 life span of neonatal RBCs (60 to 70 days vs 120 days in adults), causes Hb concentration to fall over the first 2 to 3 mo of life, usually to no lower than 9.4 g/dL. Hb remains stable over the next several weeks, and then slowly rises in the 4th to 6th mo secondary to renewed erythropoietin stimulation.
The same mechanism causes anemia in preterm infants during the first 4 to 12 wk, but lower erythropoietin production, shorter RBC life span (35 to 50 days), rapid growth, and more frequent phlebotomy contribute to a faster and 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, absolute blood volume is low (eg, preterm, 90 to 105 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 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. When significant blood transfer occurs, 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; the mechanism of hemorrhage, which is often massive and rapid, 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
Cephalhematomas resulting 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, most common among 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 caused by sepsis, vascular malformations, or prenatal maternal use of vitamin K antagonists (eg, phenytoin, warfarin, isoniazid).
Decreased RBC production
Defects in RBC production may be
Congenital defects are extremely rare, but Diamond-Blackfan anemia 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 webbed 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) may impair RBC production in the bone marrow. Congenital parvovirus B19 infection may result in the absence of RBC production.
Nutritional deficiencies of iron, copper, folate (folic acid), 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 among neonates whose mothers have an iron deficit and among premature infants who have not been transfused and 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 caused by
All also 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 severe scenario is that an Rh (D antigen)-negative mother becomes sensitized to the D antigen during a previous 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. ABO incompatibility usually occurs in type O mothers. Mothers with type A, B, or AB blood make anti-A or anti-B antibodies that are predominantly IgM and are incapable of crossing the placenta. Hemolysis caused by ABO incompatibility can occur in a first pregnancy because mothers are often sensitized by antigens in foods or bacteria.
RBC membrane disorders alter RBC shape and deformability, resulting 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).
Enzyme 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 Hb is composed of 2 α and 2 γ globin chains (fetal Hb or Hb F [α2
γ2]). After birth, γ-chain production decreases (to < 2% by 2 to 4 yr of age) and β-chain production increases until adult Hb (Hb A [α2
β2]) becomes predominant. α-Thalassemia (see Anemias Caused by Hemolysis: Thalassemias) 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 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 (eg, 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 of age.
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 hereditary disorders that may cause neonatal anemia (eg, hemoglobinopathies, enzyme deficiencies, red cell membrane disorders, RBC aplasias), and obstetric factors (eg, infections, vaginal bleeding, obstetric 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, red cell membrane disorder, or autoimmune anemia; cholecystectomy might indicate a history of hemolysis-induced 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 (caused by ABO incompatibility or G6PD deficiency) or localized (caused by breakdown of sequestered blood in cephalhematomas). Hepatosplenomegaly suggests hemolysis, congenital infection, 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 ultrasonography shows hydrops fetalis, which, by definition, 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, initial testing consists of
If the reticulocyte count is low, anemia is caused by acquired or congenital bone marrow dysfunction, and the infant should be evaluated for causes of bone marrow suppression with
If these studies do not identify a cause of anemia, a bone marrow biopsy, genetic testing for congenital disorders of RBC production, or both may be necessary.
If the reticulocyte count is elevated or normal (reflecting an appropriate bone marrow response), anemia is caused by blood loss or hemolysis. If there is no apparent blood loss or if signs of hemolysis are noted on the peripheral smear, a direct antiglobulin test (DAT [Coombs' test]) should be done.
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 show abnormal RBC morphology compatible with a membrane disorder, microangiopathy, disseminated intravascular coagulation, vitamin E deficiency, or hemoglobinopathy. If the smear is normal, blood loss, enzyme deficiency, or infection should be considered and an appropriate assessment, including testing for fetal-to-maternal hemorrhage, 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 Hb 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. The Kleihauer-Betke technique is not useful when the mother has a hemoglobinopathy.
Treatment
Need for treatment varies with degree of anemia and associated medical conditions. Mild anemia in otherwise healthy term and preterm infants generally does not require specific 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. Infants should be considered for transfusion if symptomatic due to anemia or if a decrease in tissue O2 delivery is suspected. The decision to transfuse should be based on symptoms, patient age, and degree of illness. Hct alone should not be the deciding factor regarding transfusion because some infants may be asymptomatic with lower levels and others may be symptomatic with higher levels.
Guidelines for when to transfuse vary, but one accepted set is described in Table 2: Perinatal Hematologic Disorders: Transfusion Guidelines for Infants < 4 mo.
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Table 2
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| Transfusion Guidelines for Infants < 4 mo |
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Hct
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Criteria* for Transfusion of RBCs
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< 45%
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Congenital cyanotic heart disease
Use of ECMO
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< 35%
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Use of O2 by hood at > 35% FIo2
Use of CPAP or mechanical ventilation with mean airway pressure > 6–8 cm H2O
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< 30%
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Use of any supplemental O2
Use of any CPAP or mechanical ventilation
Significant abnormalities of heart rate or respiratory rate†
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< 20%
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Low reticulocyte count and symptoms of anemia (eg, tachycardia, tachypnea, poor feeding)
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*At least 1 of these criteria must also be present.
†Abnormalities include > 6 episodes of apnea in 12 h, 2 episodes of apnea in 24 h requiring bag-and-mask ventilation (while receiving therapeutic doses of methylxanthines), heart rate > 180/min for 24 h, clinically significant bradycardia, and respiratory rate > 80/min for 24 h.
CPAP = continuous positive airway pressure; ECMO = extracorporeal membrane oxygenation; FIo2
= fractional inspired O2.
Adapted from Roseff SD, Luban NLC, Manno CS: Guidelines for assessing appropriateness of pediatric transfusion. Transfusion 42(11):1398–1413, 2002.
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Before the first 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 done 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 10 to 20 mL/kg derived from a single donation; sequential transfusions from the same unit of blood minimize recipient exposure and transfusion complications. Blood from cytomegalovirus-negative donors should be considered for extremely premature infants.
Exchange transfusion
Exchange transfusion, in which blood from the neonate is removed in aliquots in sequence with packed RBC transfusion, is indicated for some cases of hemolytic anemia with elevation of serum bilirubin and some cases of severe anemia with heart failure. This procedure decreases plasma antibody titers and bilirubin levels and minimizes fluid overload. Serious adverse effects (eg, thrombocytopenia; necrotizing enterocolitis; hypoglycemia; hypocalcemia; shock, pulmonary edema, or both [caused by shifts in fluid balance]) are common, so the procedure should be done 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 first 2 wk of life.
Iron therapy 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, so therapy should be guided by a hematologist.
Treatment of more unusual causes of anemia is disorder specific (eg, corticosteroids in Diamond-Blackfan anemia, and vitamin B12 for B12 deficiency).
Last full review/revision January 2010 by David A. Paul, MD
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