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Perinatal Anemia

By David A. Paul, MD

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(See also Evaluation of Anemia. Prenatal and perinatal changes in erythropoiesis are discussed in Perinatal Physiology.)

Anemia is a reduction in red cell mass or Hb and is usually defined as Hb or Hct > 2 standard deviations below the mean for age. Some authorities also consider a relative anemia to exist when a Hb or Hct above that cutoff point is insufficient to meet tissue oxygen demand. Anemia and polycythemia are the most common hematologic disorders diagnosed at birth.

Both Hb and Hct change rapidly as a neonate matures, so lower limits of normal also change (see Table: 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.

Age-Specific Values for Hemoglobin and Hematocrit


Hb (g/dL)

Hct (%)

28 wk gestation



32 wk gestation






1–3 days



2 wk




Causes of anemia in neonates include

  • Physiologic processes

  • Blood loss

  • Decreased 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 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 Hb concentration to fall over the first 2 to 3 mo of life (typical Hb nadir 9 to 11 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.

Physiologic anemia is more pronounced in preterm infants, 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 wk. 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) in preterm infants. Anemia of prematurity most commonly affects infants < 32 wk gestation. Almost all acutely ill and extremely preterm infants (< 28 wk 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.

Cord malformations include velamentous insertion of the umbilical cord, vasa previa, 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 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 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 resulting from procedures such as vacuum or forceps delivery are usually relatively harmless, but subgaleal bleeds can rapidly extend into soft tissue, sequestering sufficient blood volume to result in anemia, hypotension, shock, and death. Neonates with 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, most common among preterm infants (see Intracranial Hemorrhage), as well as subarachnoid and subdural bleeding also can result in a significantly lowered Hct.

Hemorrhagic disease of the newborn (see Vitamin K Deficiency) 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 h)

  • Classic (1st wk of life)

  • Late (2 to 12 wk of age)

The early form is caused by maternal use of a drug that inhibits vitamin K (eg, certain anticonvulsants; 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 (eg, hemophilia), disseminated intravascular coagulation caused by sepsis, or vascular malformations.

Decreased RBC production

Defects in RBC production may be

  • Congenital

  • Acquired

Congenital defects are extremely rare, but Diamond-Blackfan anemia and Fanconi 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 (though no 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 caused by defective stem cell differentiation.

Fanconi 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 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, rubella, syphilis, HIV, cytomegalovirus, adenovirus, bacterial sepsis) may impair RBC production in the bone marrow. Congenital parvovirus B19 and human herpesvirus 6 infections 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 may be caused by

  • Immune-mediated disorders

  • RBC membrane disorders

  • Enzyme deficiencies

  • Hemoglobinopathies

  • Infections

All also cause hyperbilirubinemia, which may cause jaundice and 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 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, < 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 is typically less severe than that caused by Rh sensitization, although some infants do develop more significant hemolysis and hyperbilirubinemia. Hemolysis caused by ABO incompatibility can occur in a first pregnancy. Mothers are often sensitized by antigens in foods or bacteria, causing an initial IgM response. Although the IgM does not cross the placenta, this sensitization causes an amnestic response that leads to IgG production when there is exposure to fetal blood during pregnancy.

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.

Enzyme deficiencies of G6PD and pyruvate kinase are the most common enzyme disorders causing hemolysis. 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 is thought to help protect against malaria and has an estimated allele frequency of 8% in malarious regions. Pyruvate kinase deficiency is an autosomal dominant disorder that occurs in all ethnic groups. Pyruvate kinase deficiency is rare and occurs in about 51 of a million whites.

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 alpha and 2 gamma globin chains (fetal Hb or Hb F [alpha2gamma2]). After birth, gamma-chain production decreases (to < 2% by 2 to 4 yr of age) and beta-chain production increases until adult Hb (Hb A [alpha2beta2]) becomes predominant. Alpha- thalassemia is a genetically inherited disorder of depressed alpha globin chain production and is the most common hemoglobinopathy causing anemia in the neonatal period. 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], Hb C) are not clinically 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 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.



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, alpha-thalassemia, 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.


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, Hb and Hct levels are done. If they are low, initial testing consists of

  • Reticulocyte count

  • Peripheral smear examination

If the reticulocyte count is low (it is normally elevated when Hb and Hct 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 PCR 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 (DAT [Coombs test]) should be done.

If the DAT is positive, anemia is likely secondary to Rh, ABO, or other blood group incompatibility. The DAT is always positive with Rh incompatibility but sometimes negative with ABO incompatibility. 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 (Coombs) test is usually positive when done.

If the DAT is negative, the RBC mean corpuscular volume (MCV) may prove helpful. A significantly low MCV suggests α-thalassemia or, less commonly, iron deficiency due to chronic intrauterine blood loss; these can 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 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.


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 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. 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 Transfusion Guidelines for Infants < 4 mo.

Transfusion Guidelines for Infants < 4 mo


Criteria* for Transfusion of RBCs

< 45%

Congenital cyanotic heart disease

Use of ECMO

< 35%

Use of O2 by hood at > 35% FIo2

Use of CPAP or mechanical ventilation with mean airway pressure > 6–8 cm H2O

< 30%

Use of any supplemental O2

Use of any CPAP or mechanical ventilation

Significant abnormalities of heart rate or respiratory rate

< 20%

Low reticulocyte count and symptoms of anemia (eg, tachycardia, tachypnea, poor feeding)

*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. Transfusion42(11):1398–1413, 2002.

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, 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 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).

Key Points

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

  • Causes of anemia in newborns include physiologic processes, blood loss, decreased 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.

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