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. The typical Hb nadir is 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 fourth to sixth month secondary to renewed erythropoietin stimulation. Simultaneously, the primary hemoglobin gradually switches from hemoglobin F to hemoglobin A, which improves oxygen delivery to the growing fetus.

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 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 born at < 32 weeks of gestation. Almost all acutely ill and extremely preterm infants (< 28 weeks) will develop anemia that is severe enough to require RBC transfusion during their initial hospitalization.

Anemia may develop because of prenatal, perinatal, or postpartum fetal or neonatal hemorrhage. In neonates, overall blood volume is low (1, 2); 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

• Umbilical cord malformations

• Placental abnormalities

• Diagnostic procedures

Fetal-to-maternal hemorrhage usually occurs spontaneously or may result from maternal trauma, amniocentesis, external cephalic version, or, rarely, 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 most common placental abnormalities that cause obstetric hemorrhage are placental abruption and placenta previa. These abnormalities cause maternal bleeding, but loss of placental surface area or maternal anemia may result in fetal or neonatal anemia.

Diagnostic procedures that may cause hemorrhage include amniocentesis, chorionic villus sampling, and umbilical cord blood sampling.

Perinatal hemorrhage may be caused by

• Precipitous delivery

• Trauma to the neonate or placenta

• Coagulopathies

Precipitous delivery (ie, rapid and spontaneous delivery) can cause hemorrhage due to umbilical cord tearing.

Trauma to the neonate or placenta during delivery (eg, incision of the placenta during cesarean delivery, birth trauma) occasionally occurs and may lead to hemorrhage. 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 typically 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, as well as subarachnoid bleeding and subdural bleeding, also can result in a significantly lowered hematocrit.

Hemorrhagic disease of the newborn (see also 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 3 forms:

• Early (first 24 hours)

• Classic (first week of life)

• Late (2 to 12 weeks of age)

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

Giving vitamin K 0.5 to 1 mg IM after birth rapidly activates clotting factors and prevents hemorrhagic disease of the newborn (3).

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.

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.

Preterm infants or others with neonatal complications may lose a significant amount of blood through phlebotomy for frequent blood tests (4).

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, and there is often a distinctive macrocytosis present with elevated RBC mean corpuscular volume (MCV). 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%. Diamond-Blackfan anemia 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 may occur prenatally or postnatally. Some acquired defects (eg, certain infections) have the most significant impact when they are acquired prenatally. The most common causes are

• Infections

• Nutritional deficiencies

Infections that can impair RBC production include malaria, rubella, syphilis, HIV, cytomegalovirus, adenovirus, congenital parvovirus B19, human herpesvirus 6, and bacterial sepsis.

Nutritional deficiencies of iron, copper, folate (folic acid), and, rarely vitamin E and vitamin B12 can 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 low-resource 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 sufficiently with iron; preterm infants deplete iron stores by 10 to 14 weeks if not supplemented.

Hemolysis may be caused by

• Immune-mediated disorders

• Red blood cell (RBC) membrane disorders

• Enzyme deficiencies

• Hemoglobinopathies

• Infections

All of these can also cause hyperbilirubinemia, which may cause jaundice and, if untreated, 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.

Most commonly, 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 hemolytic disease of the fetus or neonate. Less often, fetal-maternal transfusion early in a pregnancy can stimulate an IgG response that affects the current pregnancy.

Intrauterine hemolysis may be severe enough to cause hydrops or fetal death. Postnatally, the infant may have 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, only approximately 1/1000 at-risk infants of Rh-negative women develops hemolytic disease (5).

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 (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 and hereditary elliptocytosis.

Enzyme deficiencies of glucose-6-phosphate dehydrogenase (G6PD) and pyruvate kinase are the most common enzyme disorders causing hemolysis.

G6PD deficiency is an X-linked disorder. It is most common among people with African ancestry (6), occurring in > 10% of African American males (7, 8). It occurs in lower frequencies among people from the Mediterranean basin (eg, Italian, Greek, Arab, or Sephardic Jewish ancestry) and people with Asian ancestry.

G6PD deficiency has many variants, some mild, some severe. The most common variant is class III, which is moderate in severity. G6PD deficiency is thought to help protect against malaria parasites and has an estimated allele frequency of 8% in malarious regions. In the United States, some states screen newborns for G6PD deficiency (by DNA testing or by measuring enzyme activity).

Pyruvate kinase deficiency is an autosomal recessive disorder that is more prevalent among European populations and, in the United States, 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 United States.

Hemoglobinopathies 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 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], 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 (9). In malaria, 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.

1. 1. Roseff SD, Luban NL, Manno CS. Guidelines for assessing appropriateness of pediatric transfusion. Transfusion. 2002;42(11):1398-1413. doi:10.1046/j.1537-2995.2002.00208.x

2. 2. Nadler SB, Hidalgo JH, Bloch T. Prediction of blood volume in normal human adults. Surgery. 1962;51(2):224-232.

3. 3. Hand I, Noble L, Abrams SA. Vitamin K and the Newborn Infant. Pediatrics. 2022;149(3):e2021056036. doi:10.1542/peds.2021-056036

4. 4. Widness JA. Pathophysiology of Anemia During the Neonatal Period, Including Anemia of Prematurity. Neoreviews. 2008;9(11):e520. doi:10.1542/neo.9-11-e520

5. 5. Practice Bulletin No. 181: Prevention of Rh D Alloimmunization. Obstet Gynecol. 2017;130(2):e57-e70. doi:10.1097/AOG.0000000000002232

6. 6. Nkhoma ET, Poole C, Vannappagari V, Hall SA, Beutler E. The global prevalence of glucose-6-phosphate dehydrogenase deficiency: a systematic review and meta-analysis. Blood Cells Mol Dis 2009;42(3):267-278. doi:10.1016/j.bcmd.2008.12.005

7. 7. Chinevere TD, Murray CK, Grant E Jr, Johnson GA, Duelm F, Hospenthal DR. Prevalence of glucose-6-phosphate dehydrogenase deficiency in U.S. Army personnel. Mil Med 2006;171(9):905-907. doi:10.7205/milmed.171.9.905

8. 8. Heller P, Best WR, Nelson RB, Becktel J. Clinical implications of sickle-cell trait and glucose-6-phosphate dehydrogenase deficiency in hospitalized black male patients. N Engl J Med 1979;300(18):1001-1005. doi:10.1056/NEJM197905033001801

9. 9. Aher S, Malwatkar K, Kadam S. Neonatal anemia. Semin Fetal Neonatal Med. 2008;13(4):239-247. doi:10.1016/j.siny.2008.02.009

History should focus on maternal factors (eg, Rh (D antigen)-negative blood type, bleeding diatheses, hereditary red blood cell [RBC] disorders, nutritional deficiencies, medications), 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, and ancestry (as a risk factor for certain hereditary anemias).

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 such as in cephalhematomas).

Hepatosplenomegaly suggests hemolysis, congenital infection, or heart failure.

Hematomas, ecchymoses, or petechiae suggest bleeding diathesis or trauma.

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, additional testing should include

• 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 may be 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 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 (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 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.

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).

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, 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).

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. General 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/day of elemental iron) beginning at 4 months of age until iron-containing solid foods are introduced at about 6 months of age (2).

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

1. 1. New HV, Berryman J, Bolton-Maggs PH, et al: Guidelines on transfusion for fetuses, neonates and older children. Br J Haematol 175(5):784–828, 2016. doi: 10.1111/bjh.14233

2. 2. Baker RD, Greer FR, Committee on Nutrition American Academy of Pediatrics: Clinical report—Diagnosis and prevention of iron deficiency and iron-deficiency anemia in infants and young children (0–3 years of age). Pediatrics 126(5):1040–1050, 2010. doi: 10.1542/peds.2010-2576