Perinatal 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]). This is called the physiologic nadir. 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 Preterm Infants An infant born before 37 weeks of gestation is considered preterm. In 2021 in the United States, 10.48% of births were preterm ( 1), and in 2018, 26.53% of births were early term (significantly... 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 Preterm, Very Preterm, and Extremely Preterm Infants An infant born before 37 weeks of gestation is considered preterm. In 2021 in the United States, 10.48% of births were preterm ( 1), and in 2018, 26.53% of births were early term (significantly... read more (< 28 weeks gestation) will develop anemia that is severe enough to require RBC transfusion during their initial hospitalization.

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 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 In vasa previa, membranes that contain fetal blood vessels connecting the umbilical cord and placenta overlie or are within 2 cm of the internal cervical os. Diagnosis is by ultrasonography... 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.

The 2 important placental abnormalities causing hemorrhage are placenta previa Placenta Previa Placenta previa is implantation of the placenta over or near the internal os of the cervix. It typically manifests as painless vaginal bleeding after 20 weeks gestation; the source of bleeding... read more and placental abruption Placental Abruption (Abruptio Placentae) Placental abruption (abruptio placentae) is premature separation of the placenta from the uterus, usually after 20 weeks gestation. It can be an obstetric emergency. Manifestations may include... read more .

Diagnostic procedures causing hemorrhage include amniocentesis Amniocentesis All procedures used to diagnose genetic disorders, except ultrasonography, are invasive and involve slight fetal risk. If testing detects a serious abnormality, the pregnancy can be terminated... read more , chorionic villus sampling Chorionic Villus Sampling All procedures used to diagnose genetic disorders, except ultrasonography, are invasive and involve slight fetal risk. If testing detects a serious abnormality, the pregnancy can be terminated... read more , and umbilical cord blood sampling Percutaneous Umbilical Blood Sampling All procedures used to diagnose genetic disorders, except ultrasonography, are invasive and involve slight fetal risk. If testing detects a serious abnormality, the pregnancy can be terminated... read more .

Perinatal hemorrhage may be caused by

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 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 can rapidly extend into soft tissue, sequestering sufficient blood volume to result in anemia, hypotension, shock, and death. Neonates with intracranial hemorrhage Intracranial Hemorrhage in Neonates 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 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 , 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 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 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 or fat malabsorption. Risk of bleeding is increased by use of coumarin anticoagulants. Deficiency is particularly common among breastfed... 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:

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.

Other possible causes of hemorrhage in the first few days of life are other coagulopathies Overview of Coagulation Disorders Abnormal bleeding can result from disorders of the coagulation system, of platelets, or of blood vessels. Disorders of coagulation can be acquired or hereditary. The major causes of acquired... read more (eg, hemophilia Hemophilia Hemophilias are common hereditary bleeding disorders caused by deficiencies of either clotting factor VIII or IX. The extent of factor deficiency determines the probability and severity of bleeding... read more ), disseminated intravascular coagulation Disseminated Intravascular Coagulation (DIC) Disseminated intravascular coagulation (DIC) involves abnormal, excessive generation of thrombin and fibrin in the circulating blood. During the process, increased platelet aggregation and coagulation... read more caused by 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 , or vascular malformations.

Defects in RBC production may be

Congenital defects are extremely rare, but the most common are

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 Microcephaly Microcephaly is a head circumference < 2 standard deviations below the mean for age. (See also Introduction to Congenital Craniofacial and Musculoskeletal Disorders and Overview of Congenital... read more , cleft palate Cleft Lip and Cleft Palate An oral-facial cleft is a birth defect in which the lip, the roof of the mouth, or both do not close in the midline and remain open, creating a cleft lip and/or cleft palate. These defects are... read more , 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 (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... 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... read more , 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 , 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 , 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 (Parvovirus B19 Infection) Erythema infectiosum is caused by acute infection with human parvovirus B19. In children, it causes mild constitutional symptoms and a blotchy or maculopapular rash beginning on the cheeks and... read more 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 is contained mainly in animal products. It is absorbed much better than nonheme iron (eg, in plants... 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 countries with high rates of food insecurity; deficiency among adults in other countries is uncommon and usually due to fat malabsorption. The main... 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 preterm infants who have not been transfused and whose formula is not supplemented with iron; preterm infants deplete iron stores by 10 to 14 weeks if not supplemented.

Hemolysis Overview of Hemolytic Anemia 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 may be caused by

All also can cause hyperbilirubinemia Consequences of hyperbilirubinemia 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 , which may cause jaundice and, if untreated, kernicterus Kernicterus Kernicterus is brain damage caused by unconjugated bilirubin deposition in basal ganglia and brain stem nuclei. Normally, bilirubin bound to serum albumin stays in the intravascular space. However... read more .

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 Hemolytic Disease of the Fetus and Neonate Hemolytic disease of the fetus and neonate is hemolytic anemia in the fetus (or neonate, as erythroblastosis neonatorum) caused by transplacental transmission of maternal antibodies to fetal... 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 Hemolytic disease of the fetus and neonate is hemolytic anemia in the fetus (or neonate, as erythroblastosis neonatorum) caused by transplacental transmission of maternal antibodies to fetal... read more , < 0.11% of pregnancies in Rh-negative women are affected.

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. Unlike Rh-mediated hemolysis, the direct antiglobulin test Direct Antiglobulin (Direct Coombs) Test (DAT [Coombs test]) may be negative in newborns with hemolysis.

RBC membrane disorders alter RBC shape and deformability and cause increased fragility, resulting in premature destruction and/or removal of RBCs from the circulation. The most common disorders are hereditary spherocytosis Hereditary Spherocytosis and Hereditary Elliptocytosis Hereditary spherocytosis and hereditary elliptocytosis are congenital red blood cell (RBC) membrane disorders that can cause a mild hemolytic anemia. Symptoms, generally milder in hereditary... read more and hereditary elliptocytosis Hereditary Spherocytosis and Hereditary Elliptocytosis Hereditary spherocytosis and hereditary elliptocytosis are congenital red blood cell (RBC) membrane disorders that can cause a mild hemolytic anemia. Symptoms, generally milder in hereditary... read more .

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 people with African ancestry that can result in hemolysis after acute illnesses or intake of oxidant... read more 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 White people; 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 with 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 people with African ancestry. It is caused by homozygous inheritance of genes for hemoglobin... read more ], 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... 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.

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 Gestational Age Gestational age and growth parameters help identify the risk of neonatal pathology. Gestational age is the primary determinant of organ maturity. Neonatal gestational age is usually defined... read more at delivery, age at presentation, sex, race, and ethnicity.

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.

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

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 may be 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 may be 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 (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 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, the 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.

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.

Guidelines for when to transfuse vary, but one accepted set is described in table Transfusion Thresholds for Infants < 4 Months Transfusion Guidelines for Infants < 4 Months .

Within the first 4 months, before the first transfusion, if not already done, maternal and fetal blood should be tested for both ABO and Rh types determination and to detect the presence of atypical RBC antibodies. Antibody screening should be done on the maternal sample when available, and a DAT should be done on the infant’s RBCs.

RBCs for neonatal transfusion must be ABO- and D-compatible with both maternal and neonatal groups and must be indirect antiglobulin test crossmatch–compatible with clinically significant RBC antibodies present in maternal or neonatal plasma. Units that are ABO compatible with both mother and neonate must be used even if the pretransfusion DAT is negative. Typically, group O D-negative RBCs are used for most neonatal top-up and exchange transfusions. If group-specific RBCs are used, which is most common for elective large-volume transfusions, they must be ABO- and D-compatible with both maternal and neonatal groups. Group-identical units should be used when possible for elective large-volume transfusions in infants to minimize the use of group O D-negative RBCs (1 Treatment references 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 ).

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 preterm infants.

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.

An exchange transfusion of a single blood volume (80 to 100 mL/kg, depending on gestational age) removes about 75% of neonatal RBCs, and a double-volume exchange (160 to 200 mL/kg) removes up to 85 to 90% of RBCs and up to 50% of circulating bilirubin (1 Treatment references 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 ).

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.

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 (2 Treatment references 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).