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Perinatal Anemia

By

Andrew W. Walter

, MS, MD, Sidney Kimmel Medical College at Thomas Jefferson University

Last full review/revision Oct 2020| Content last modified Oct 2020
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Both hemoglobin and hematocrit change rapidly as a neonate matures, so lower limits of normal also change (see Table: Age-Specific Values for Hemoglobin and Hematocrit Age-Specific Values for Hemoglobin and Hematocrit Anemia is a reduction in red cell mass or hemoglobin and is usually defined as hemoglobin or hematocrit > 2 standard deviations below the mean for age. Some authorities also consider a relative... read more ). Variables such as gestational age Gestational Age Gestational age and growth parameters help identify the risk of neonatal pathology. Gestational age is the primary determinant of organ maturity. Gestational age is loosely defined as the number... read more , sampling site (capillary vs vein), 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), and timing of cord clamping (greater delay transfers more blood to the neonate) also affect results.

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Etiology of Perinatal Anemia

Causes of anemia in neonates include

  • Physiologic processes

  • Blood loss

  • Decreased red blood cell (RBC) production

  • Increased RBC destruction (hemolysis)

Physiologic anemia

Physiologic anemia is the most common cause of anemia in the neonatal period. Normal physiologic processes often cause normocytic-normochromic anemia at an expected time after birth 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 oxygen level, resulting in negative feedback on erythropoietin production and erythropoiesis. This reduction in erythropoiesis, as well as the shorter life span of neonatal RBCs (90 days vs 120 days in adults), causes hemoglobin (Hb) concentration to fall over the first 2 to 3 months of life (typical Hb nadir 9 to 11 g/dL [90 to 110 g/L]). Hb remains stable over the next several weeks and then slowly rises in the 4th to 6th month secondary to renewed erythropoietin stimulation.

Physiologic anemia is more pronounced in preterm infants Premature Infants An infant born before 37 weeks gestation is considered premature. Prematurity is defined by the gestational age at which infants are born. Previously, any infant weighing read more , occurring earlier and with a lower nadir compared to term infants. This condition is also referred to as anemia of prematurity. A mechanism similar to the one that causes anemia in term infants causes anemia in preterm infants during the first 4 to 12 weeks. 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 [80 to 100 g/L]) in preterm infants. Anemia of prematurity most commonly affects infants < 32 weeks gestation. Almost all acutely ill and extremely preterm infants Premature, Very Preterm, and Extremely Preterm Infants An infant born before 37 weeks gestation is considered premature. Prematurity is defined by the gestational age at which infants are born. Previously, any infant weighing read more (< 28 weeks gestation) will develop anemia that is severe enough to require RBC transfusion during their initial hospitalization.

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

  • Twin-to-twin transfusion

  • Cord malformations

  • Placental abnormalities

  • Diagnostic procedures

Fetal-to-maternal hemorrhage usually occurs spontaneously or may result from 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 Perinatal Polycythemia and Hyperviscosity Syndrome Polycythemia is an abnormal increase in red blood cell mass, defined in neonates as a venous hematocrit ≥ 65%; this increase can lead to hyperviscosity with sludging of blood within vessels... read more .

Cord malformations include velamentous insertion of the umbilical cord, vasa previa Vasa Previa Vasa previa occurs when membranes that contain fetal blood vessels connecting the umbilical cord and placenta overlie or are within 2 cm of the internal cervical os. Vasa previa can occur on... read more , or abdominal or placental insertion; the mechanism of hemorrhage, which is often massive, rapid, and life threatening, is by cord vessel shearing or rupture.

Perinatal hemorrhage may be caused by

  • Precipitous delivery (ie, rapid and spontaneous delivery, which causes hemorrhage due to umbilical cord tearing)

  • Obstetric accidents (eg, incision of the placenta during cesarean delivery, birth trauma)

  • Coagulopathies

Cephalhematomas Cephalhematoma The forces of labor and delivery occasionally cause physical injury to the infant. The incidence of neonatal injury resulting from difficult or traumatic deliveries is decreasing due to increasing... read more Cephalhematoma resulting from procedures such as vacuum or forceps delivery are usually relatively harmless, but subgaleal bleeds Subgaleal hemorrhage The forces of labor and delivery occasionally cause physical injury to the infant. The incidence of neonatal injury resulting from difficult or traumatic deliveries is decreasing due to increasing... read more Subgaleal hemorrhage can rapidly extend into soft tissue, sequestering sufficient blood volume to result in anemia, hypotension, shock, and death. Neonates with intracranial hemorrhage Intracranial Hemorrhage The forces of labor and delivery occasionally cause physical injury to the infant. The incidence of neonatal injury resulting from difficult or traumatic deliveries is decreasing due to increasing... read more Intracranial Hemorrhage can lose sufficient blood into their intracranial vault to cause anemia and sometimes hemodynamic compromise (unlike older children who have a lower head-to-body ratio and in whom intracranial hemorrhage is limited in volume because the fused cranial sutures do not allow the skull to expand; instead, intracranial pressure increases and stops the bleeding). Far less often, rupture of the liver, spleen, or adrenal gland during delivery may lead to internal bleeding. Intraventricular hemorrhage Intraventricular hemorrhage and/or intraparenchymal hemorrhage The forces of labor and delivery occasionally cause physical injury to the infant. The incidence of neonatal injury resulting from difficult or traumatic deliveries is decreasing due to increasing... read more Intraventricular hemorrhage and/or intraparenchymal hemorrhage , most common among preterm infants, as well as subarachnoid bleeding Subarachnoid hemorrhage The forces of labor and delivery occasionally cause physical injury to the infant. The incidence of neonatal injury resulting from difficult or traumatic deliveries is decreasing due to increasing... read more Subarachnoid hemorrhage and subdural bleeding Subdural hemorrhage The forces of labor and delivery occasionally cause physical injury to the infant. The incidence of neonatal injury resulting from difficult or traumatic deliveries is decreasing due to increasing... read more Subdural hemorrhage also can result in a significantly lowered hematocrit.

Hemorrhagic disease of the newborn (see also Vitamin K Deficiency Vitamin K Deficiency Vitamin K deficiency results from extremely inadequate intake, fat malabsorption, or use of coumarin anticoagulants. Deficiency is particularly common among breastfed infants. It impairs clotting... read more ) is hemorrhage within a few days of a normal delivery caused by transient physiologic deficiency in vitamin K–dependent coagulation factors (factors II, VII, IX, and X). These factors are poorly transferred across the placenta, and, because vitamin K is synthesized by intestinal bacteria, very little is produced in the initially sterile intestine of the newborn. Vitamin K–deficient bleeding has three forms:

  • Early (1st 24 hours)

  • Classic (1st week of life)

  • Late (2 to 12 weeks of age)

The early form is caused by maternal use of a drug that inhibits vitamin K (eg, certain antiseizure drugs; isoniazid; rifampin; warfarin; prolonged maternal use of broad-spectrum antibiotics, which suppresses bowel bacterial colonization).

The classic form occurs in neonates who do not receive vitamin K supplementation after birth.

The late form occurs in exclusively breastfed neonates who do not receive vitamin K supplementation after birth. Giving vitamin K 0.5 to 1 mg IM after birth rapidly activates clotting factors and prevents hemorrhagic disease of the newborn.

Decreased red blood cell (RBC) production

Defects in RBC production may be

  • Congenital

  • Acquired

Congenital defects are extremely rare, but the most common are

  • Diamond-Blackfan anemia

  • Fanconi anemia

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 (though not always) 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 a ribosomopathy caused by defective stem cell differentiation.

Fanconi anemia is an autosomal recessive disorder of bone marrow progenitor cells that causes a bone marrow failure syndrome with 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 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

  • Nutritional deficiencies

Infections (eg, malaria Malaria Malaria is infection with Plasmodium species. Symptoms and signs include fever (which may be periodic), chills, rigors, sweating, diarrhea, abdominal pain, respiratory distress, confusion, seizures... read more , rubella Congenital Rubella Congenital rubella is a viral infection acquired from the mother during pregnancy. Signs are multiple congenital anomalies that can result in fetal death. Diagnosis is by serology and viral... read more , syphilis Congenital Syphilis Congenital syphilis is a multisystem infection caused by Treponema pallidum and transmitted to the fetus via the placenta. Early signs are characteristic skin lesions, lymphadenopathy, hepatosplenomegaly... read more Congenital Syphilis , HIV Human Immunodeficiency Virus (HIV) Infection in Infants and Children Human immunodeficiency virus (HIV) infection is caused by the retrovirus HIV-1 (and less commonly by the related retrovirus HIV-2). Infection leads to progressive immunologic deterioration and... read more Human Immunodeficiency Virus (HIV) Infection in Infants and Children , cytomegalovirus Congenital and Perinatal Cytomegalovirus Infection (CMV) Cytomegalovirus infection may be acquired prenatally or perinatally and is the most common congenital viral infection. Signs at birth, if present, are intrauterine growth restriction, prematurity... read more Congenital and Perinatal Cytomegalovirus Infection (CMV) , adenovirus Adenovirus Infections Infection with one of the many adenoviruses may be asymptomatic or result in specific syndromes, including mild respiratory infections, keratoconjunctivitis, gastroenteritis, cystitis, and primary... read more , bacterial sepsis Neonatal Sepsis Neonatal sepsis is invasive infection, usually bacterial, occurring during the neonatal period. Signs are multiple, nonspecific, and include diminished spontaneous activity, less vigorous sucking... read more ) may impair RBC production in the bone marrow. Congenital parvovirus B19 Erythema Infectiosum Erythema infectiosum, acute infection with parvovirus B19, causes mild constitutional symptoms and a blotchy or maculopapular rash beginning on the cheeks and spreading primarily to exposed... read more Erythema Infectiosum and human herpesvirus 6 infections may result in decreased RBC production.

Nutritional deficiencies of iron Iron Deficiency Iron (Fe) is a component of hemoglobin, myoglobin, and many enzymes in the body. Heme iron, contained mainly in animal products, is absorbed much better than nonheme iron (eg, in plants and... read more , copper Acquired Copper Deficiency Copper is a component of many body proteins; almost all of the body’s copper is bound to copper proteins. Copper deficiency may be acquired or inherited. (See also Overview of Mineral Deficiency... read more , folate Folate Deficiency Folate deficiency is common. It may result from inadequate intake, malabsorption, or use of various drugs. Deficiency causes megaloblastic anemia (indistinguishable from that due to vitamin... read more (folic acid), vitamin E Vitamin E Deficiency Dietary vitamin E deficiency is common in developing countries; deficiency among adults in developed countries is uncommon and usually due to fat malabsorption. The main symptoms are hemolytic... read more , and vitamin B12 Vitamin B12 Deficiency Dietary vitamin B12 deficiency usually results from inadequate absorption, but deficiency can develop in vegans who do not take vitamin supplements. Deficiency causes megaloblastic anemia, damage... read more 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 weeks if not supplemented.

Hemolysis

  • Immune-mediated disorders

  • Red blood cell (RBC) membrane disorders

  • Enzyme deficiencies

  • Hemoglobinopathies

  • Infections

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 by fetal-to-maternal passage of blood; a later pregnancy with an Rh-positive fetus may then prompt an anamnestic maternal IgG response when the mother is re-exposed to fetal blood during this later pregnancy that may result in fetal and neonatal hemolysis (see Erythroblastosis Fetalis Erythroblastosis Fetalis Erythroblastosis fetalis is hemolytic anemia in the fetus (or neonate, as erythroblastosis neonatorum) caused by transplacental transmission of maternal antibodies to fetal red blood cells.... read more ). Less often, fetal-maternal transfusion early in a pregnancy can stimulate an IgG response that affects that pregnancy. Intrauterine hemolysis may be severe enough to cause hydrops or fetal 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 Prevention Erythroblastosis fetalis is hemolytic anemia in the fetus (or neonate, as erythroblastosis neonatorum) caused by transplacental transmission of maternal antibodies to fetal red blood cells.... read more , < 0.11% of pregnancies in Rh-negative women are affected.

Pearls & Pitfalls

  • Rarely, fetal-maternal transfusion early in a pregnancy can stimulate an IgG response that causes hemolysis during that pregnancy.

ABO incompatibility may cause hemolysis by a similar mechanism. Mothers are sensitized by antigens present in their food or intestinal flora that are homologous to A and B antigens (thus, a prior pregnancy is not necessary for sensitization). These exogenous antigens trigger a maternal IgM response depending on the mother's blood type. The response is anti-A if the mother is type B, anti-B if the mother is type A, or both if the mother is type O. These IgM antibodies do not cross the placenta. However, when incompatible fetal blood gets into the maternal circulation, an anamnestic IgG response occurs, and these anti-A or anti-B IgG antibodies are capable of crossing the placenta in large amounts and causing hemolysis in the fetus. ABO incompatibility usually is less severe than Rh incompatibility because the initial IgM antibodies clear at least some of the fetal blood cells from the maternal circulation before IgG antibody production can occur, and there is less ABO antigen on the fetal RBC membrane than Rh antigen.

Enzyme deficiencies of glucose-6-phosphate dehydrogenase (G6PD) and pyruvate kinase are the most common enzyme disorders causing hemolysis. G6PD deficiency Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked enzymatic defect common in blacks, which can result in hemolysis after acute illnesses or intake of oxidant drugs (including... read more Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency is a sex-linked disorder common among people of Mediterranean, Middle Eastern, African, and Asian ancestry and affects > 400 million people worldwide. It has many subtypes, some mild, some severe. The most common variant is the A- type, which is moderate in severity. G6PD deficiency is thought to help protect against malaria and has an estimated allele frequency of 8% in malarious regions. In the US, some states screen newborns for G6PD deficiency (by DNA testing or by measuring enzyme activity). Pyruvate kinase deficiency Glycolytic Pathway Defects Glycolytic pathway defects are autosomal recessive red blood cell metabolic disorders that cause hemolytic anemia. (See also Overview of Hemolytic Anemia.) The glycolytic pathway is one of the... read more is an autosomal recessive disorder that is more prevalent among European populations and, in the US, the Pennsylvania Dutch. Pyruvate kinase deficiency is rare and occurs in about 1 of 20,000 whites; screening for this disorder is not routinely done in the US.

Hemoglobinopathies Overview of Hemoglobinopathies Hemoglobinopathies are genetic disorders affecting the structure or production of the hemoglobin molecule. Hemoglobin molecules consist of polypeptide chains whose chemical structure is genetically... read more are caused by deficiencies and structural abnormalities of globin chains. At birth, 55 to 90% of the neonate’s hemoglobin (Hb) is fetal hemoglobin (Hb F), which is composed of 2 alpha and 2 gamma globin chains (alpha2gamma2). After birth, gamma-chain production decreases (to < 2% by 2 to 4 years of age) and beta-chain production increases until adult hemoglobin (Hb A, alpha2beta2) becomes predominant. Alpha-thalassemia Thalassemias Thalassemias are a group of inherited microcytic, hemolytic anemias characterized by defective hemoglobin synthesis. Alpha-thalassemia is particularly common among people of African, Mediterranean... read more is a genetically inherited disorder of depressed alpha globin chain production and is the most common hemoglobinopathy causing anemia. Beta-thalassemia is an inherited decrease in beta-chain production. Because beta globin is naturally low at birth, beta-thalassemia and structural abnormalities of the beta globin chain (eg, Hb S [sickle cell disease Sickle Cell Disease Sickle cell disease (a hemoglobinopathy) causes a chronic hemolytic anemia occurring almost exclusively in blacks. It is caused by homozygous inheritance of genes for hemoglobin (Hb) S. Sickle-shaped... read more Sickle Cell Disease ], Hb C) are not clinically apparent at birth and symptoms do not appear until fetal hemoglobin levels have fallen to sufficiently low levels at 3 to 4 months of age and are replaced by adult hemoglobin containing either a pathologic mutation in the beta chain (as in sickle cell anemia) or a decreased percentage of beta chain (as in beta-thalassemia).

Intrauterine infections by certain bacteria, viruses, fungi, and protozoa (most notably malaria) also may trigger hemolytic anemia. In malaria Malaria Malaria is infection with Plasmodium species. Symptoms and signs include fever (which may be periodic), chills, rigors, sweating, diarrhea, abdominal pain, respiratory distress, confusion, seizures... read more , the Plasmodium parasite invades and ultimately ruptures the RBCs. 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 of Perinatal Anemia

Symptoms and signs of perinatal anemia 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 of Perinatal Anemia

History

History should focus on maternal factors (eg, bleeding diatheses, hereditary red blood cell [RBC] disorders, nutritional deficiencies, drugs), family history of hereditary disorders that may cause neonatal anemia (eg, alpha-thalassemia, enzyme deficiencies, RBC 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. History of anemia in the parents should be sought. Splenectomy would indicate a possible history of hemolysis, RBC 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 Rh or 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 increased middle cerebral artery peak systolic velocity or hydrops fetalis, which, by definition, is abnormal, excessive fluid in ≥ 2 body compartments (eg, pleura, peritoneum, pericardium); cardiac, hepatic, and splenic enlargement may be present.

After birth, if anemia is suspected, a complete blood count is done; if hemoglobin and hematocrit levels are low, initial testing consists of

  • Reticulocyte count

  • Peripheral smear examination

If anemia is acute, urgent intervention may be required.

If the reticulocyte count is low (it is normally elevated when hemoglobin and hematocrit are low), anemia is caused by acquired or congenital bone marrow dysfunction, and the infant should be evaluated for causes of bone marrow suppression with

  • Titers or polymerase chain reaction studies for congenital infection (rubella, syphilis, HIV, cytomegalovirus, adenovirus, parvovirus, human herpesvirus 6)

  • Folate and vitamin B12 levels

  • Iron and copper levels

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 or the serum bilirubin level is elevated (which may occur with hemolysis), a direct antiglobulin test Direct Antiglobulin (Direct Coombs) Test At the end of their normal life span (about 120 days), red blood cells (RBCs) are removed from the circulation. Hemolysis is defined as premature destruction and hence a shortened RBC life span ( read more Direct Antiglobulin (Direct Coombs) Test (DAT [Coombs test]) should be done.

If the direct antiglobulin test is positive, anemia is likely secondary to Rh, ABO, or other blood group incompatibility. The DAT is always positive with Rh incompatibility but is sometimes negative with ABO incompatibility because there is less ABO antigen on the RBC membrane than Rh antigen. Infants may have active hemolysis caused by ABO incompatibility and have a negative DAT; however, in such infants, the peripheral blood smear should reveal microspherocytes, and the indirect antiglobulin (indirect Coombs) test Indirect Antiglobulin (Indirect Coombs) Test At the end of their normal life span (about 120 days), red blood cells (RBCs) are removed from the circulation. Hemolysis is defined as premature destruction and hence a shortened RBC life span ( read more Indirect Antiglobulin (Indirect Coombs) Test is usually positive because it identifies plasma ABO antibodies, which, in the presence of adult RBCs (adult RBCs have well discriminated ABO antigens), give a positive test result.

If the direct antiglobulin test is negative, the RBC mean corpuscular volume (MCV) may prove helpful, although because fetal RBCs are normally larger than adult RBCs, it can be challenging to interpret MCV in the neonate. However, a significantly low MCV suggests alpha-thalassemia or, less commonly, iron deficiency due to chronic intrauterine blood loss; these may be distinguished by red cell distribution width (RDW), which is often normal with thalassemia but elevated with iron deficiency. 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. Infants with hereditary spherocytosis often have an elevated mean corpuscular hemoglobin concentration (MCHC). 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 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. The Kleihauer-Betke technique is not useful when the mother has a hemoglobinopathy.

Treatment of Perinatal Anemia

Need for treatment of perinatal anemia 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 oxygen delivery is suspected. The decision to transfuse should be based on symptoms, patient age, and degree of illness. Hematocrit 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.

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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 months 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 Exchange transfusion Jaundice is a yellow discoloration of the skin and eyes caused by hyperbilirubinemia (elevated serum bilirubin concentration). The serum bilirubin level required to cause jaundice varies with... read more , 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, some cases of severe anemia with heart failure, and cases when infants with chronic blood loss are euvolemic. 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 weeks of life.

Iron therapy is given to infants who have blood loss (eg, due to hemorrhagic diathesis, gastrointestinal bleeding, frequent phlebotomy). Oral iron supplements are preferred. Parenteral iron may rarely cause anaphylaxis. The American Academy of Pediatrics (AAP) recommends giving breastfed infants a daily liquid iron supplement (1 mg/kg of elemental iron) beginning at 4 months of age until iron-containing solid foods are introduced at about 6 months of age (1 Treatment reference Anemia is a reduction in red cell mass or hemoglobin and is usually defined as hemoglobin or hematocrit > 2 standard deviations below the mean for age. Some authorities also consider a relative... read more ).

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

Treatment reference

Key Points

  • Anemia is a reduction in red cell mass or hemoglobin, and in neonates is usually defined as hemoglobin or hematocrit > 2 standard deviations below the mean for age.

  • Causes of anemia in newborns include physiologic processes, blood loss, decreased red blood cell (RBC) production, and increased RBC destruction.

  • Physiologic anemia is the most common cause of anemia in the neonatal period and does not generally require extensive evaluation or treatment.

  • Neonates with anemia are generally pale and, if anemia is severe, have tachypnea, tachycardia, and sometimes a flow murmur.

  • 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.

Drugs Mentioned In This Article

Drug Name Select Trade
LANIAZID
COUMADIN
RIFADIN, RIMACTANE
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