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Alloimmune hemolytic disease of the newborn: Postnatal diagnosis and management

Alloimmune hemolytic disease of the newborn: Postnatal diagnosis and management
Literature review current through: Jan 2024.
This topic last updated: Mar 08, 2023.

INTRODUCTION — Alloimmune hemolytic disease of the newborn (HDN, also known as hemolytic disease of the fetus and newborn [HDFN]), is caused by the destruction of red blood cells (RBCs) of the neonate or fetus by maternal immunoglobulin G (IgG) antibodies. These antibodies are produced when an RBC antigen not expressed in the mother, gains access to the maternal circulation, either from a gestating fetus or other exogenous source (transfusion). This process is referred to as sensitization.

The postnatal diagnosis and management of alloimmune HDN in the newborn will be reviewed here. Prenatal diagnosis and management are discussed separately. (See "Management of non-RhD red blood cell alloantibodies during pregnancy" and "RhD alloimmunization in pregnancy: Overview".)

TYPES OF HDN — Alloimmune HDN primarily involves the major blood groups of Rhesus (Rh), A, B, AB, and O, although minor blood group incompatibilities (Kell, Duffy, MNS, P, and Diego systems) can also result in significant disease (table 1) [1]. (See "Red blood cell antigens and antibodies".)

Only maternal immunoglobulin G (IgG) causes HDN, because transfer of maternal antibodies across the placenta depends upon the fragment crystallizable (Fc) component of the IgG molecule, which is not present in immunoglobulin A (IgA) and immunoglobulin M (IgM). (See "Structure of immunoglobulins", section on 'IgG'.)

RhD hemolytic disease — Individuals are classified as Rhesus (Rh) negative or positive based upon the expression of the major D antigen on the erythrocyte. The original description of HDN was due to RhD incompatibility, which is associated with the most severe form of the disease (hydrops fetalis).

Rh negative is the result of either an absence of the RHD gene (seen in White individuals of European ancestry) or alterations in the RHD gene, resulting in gene inactivation (seen in individuals of African ancestry). (See "Red blood cell antigens and antibodies", section on 'Rh blood group system'.)

Maternal sensitization in an RhD-negative individual is due to a previous exposure to Rh antigen, either through transfusion with Rh-positive red blood cells (RBCs) or pregnancy with a Rh-positive offspring. Thus, in the absence of a transfusion history, Rh HDN generally does not occur in the first pregnancy. The introduction of antenatal Rh(D) immune globulin prophylaxis has significantly reduced alloimmune sensitization in pregnant women who are RhD negative. (See "RhD alloimmunization: Prevention in pregnant and postpartum patients".)

In the affected neonate, clinical manifestations of RhD HDN range from mild, self-limited hemolytic disease to severe, life-threatening anemia (eg, hydrops fetalis). The severity of HDN increases with successive pregnancies. Hyperbilirubinemia usually occurs within the first 24 hours of life. (See 'Clinical presentation' below.)

However, in utero interventions for affected pregnancies, including intrauterine transfusions and early delivery, have reduced the severity of disease in the newborn, resulting in decreased neonatal morbidity and mortality rates. (See "RhD alloimmunization in pregnancy: Overview".)

ABO hemolytic disease — There are four major phenotypes in the ABO system (A, B, AB, and O). At approximately three to six months of age, individuals naturally begin to make A and/or B antibodies to the antigens they do not possess since these antigens are found ubiquitously in food and bacteria. As a result, ABO HDN can occur with the first pregnancy and occurs primarily in mothers with blood type O [2,3].

Although ABO incompatibility occurs in approximately 15 percent of all pregnancies, it usually does not result in clinically significant hemolytic disease. HDN occurs in only 4 percent of pregnancies with ABO incompatibility (ie, 0.6 percent of all pregnancies). ABO HDN is more common and severe in infants of African descent [4]. Infants with ABO HDN generally have less severe disease than those with RhD disease, but severe cases can occur when maternal anti-A or anti-B levels are exceptionally high [4-10].

Affected infants with ABO HDN are usually asymptomatic at birth and have either no or mild anemia. They generally develop hyperbilirubinemia within the first 24 hours of birth. Phototherapy is usually sufficient therapy for most infants with ABO HDN [1]. Hydrops fetalis is rare, and clinically significant hemolysis is uncommon, as <0.1 percent of infants with evidence of hemolysis will require exchange transfusions [4,11].

For neonates with ABO HDN who present with severe hemolysis (eg, hydrops fetalis, total serum bilirubin [TSB] ≥25 mg/dL, readmission for jaundice, signs of bilirubin neurotoxicity), other causes of jaundice should be sought since ABO HDN alone is unlikely to cause this degree of hemolysis. (See 'Differential diagnosis' below.)

With the advent of universal newborn bilirubin screening, one center observed that neonates born to mothers with blood group O had similarly low rates of severe hyperbilirubinemia (TSB ≥25 mg/dL) regardless of whether the neonate had blood group O or group A or B [12]. In a follow-up report, the same investigators concluded that the lack of severe hyperbilirubinemia among neonates with ABO incompatibility in their earlier report may be explained, at least in part, by greater use of phototherapy among neonates born to mothers with blood group O [13]. These observations suggest that it may not be necessary to routinely perform blood typing and other testing for every infant born to a mother with blood group O at centers where all newborns undergo universal screening for hyperbilirubinemia [12,13].

Other blood group antibodies — Thirty-three total blood group systems, which include more than 300 antigens, are recognized by the International Society of Blood Transfusion (ISBT). Several blood groups other than those of the ABO and Rh group are associated with HDN and include Kell, Duffy, MNS, P, and others (table 1). The distribution of blood group antigens varies between different racial and ethnic groups [14]. Antibodies may develop in response to exposure to these antigens from a previous transfusion or pregnancy or from exposure to bacteria or viruses that express these antigens. (See "Management of non-RhD red blood cell alloantibodies during pregnancy".)

Although RhD incompatibility remains the most frequent cause of Rh HDN, some of the other more than 44 Rh antigens, particularly E and C, have been associated with HDN (table 1) [15]. (See "Red blood cell antigens and antibodies", section on 'Rh blood group system'.)

The clinical disease associated with HDN due to these other blood groups ranges from mild (hyperbilirubinemia) to severe, including hydrops fetalis. The variability is, in part, dependent upon the blood group (table 1). In particular, anti-Kell HDN can be severe and may require intrauterine intervention. (See "Management of non-RhD red blood cell alloantibodies during pregnancy".)

CLINICAL PRESENTATION — Clinical manifestations of HDN range from mild, self-limited hemolytic disease (eg, hyperbilirubinemia with mild to moderate anemia) to severe, life-threatening anemia (eg, hydrops fetalis).

Mild to moderate disease — Most newborns with HDN have mild to moderate disease, which typically presents as self-limited hemolytic disease.

Characteristic clinical and laboratory findings The characteristic finding of HDN is early onset of jaundice and unconjugated hyperbilirubinemia within the first 24 hours after birth. Affected newborns may also have symptomatic anemia (eg, lethargy, tachycardia, poor feeding) but without signs of circulatory collapse.

Degree of anemia – The degree of anemia varies, depending upon the type of HDN:

Infants with ABO HDN generally have no or only minor anemia at birth. If the neonate with ABO incompatibility presents with severe hemolysis, other causes should be explored. (See 'Differential diagnosis' below.)

In contrast, infants with HDN caused by Rhesus (Rh) or some minor blood group antibodies can present with symptomatic anemia that requires red blood cell (RBC) transfusion. (See 'Early non-life-threatening disease' below.)

Other laboratory findings – Other laboratory findings that may be seen in a subset of newborns with HDN include cholestasis (ie, elevated direct bilirubin) and thrombocytopenia. Cholestasis is noted in 5 to 15 percent of affected newborns, most commonly in those treated with intrauterine transfusions (IUTs) [16,17]. Thrombocytopenia may occur in as many as one-quarter of newborns with HDN [18]. It is thought to be a secondary effect of increased erythropoiesis, which can suppress the other cell lines. Risk factors for thrombocytopenia include treatment with IUTs and lower gestational age or birth weight [18].

Hydrops fetalis — Infants with severe, life-threatening anemia can develop hydrops fetalis which is manifested by diffuse edema, pleural and/or pericardial effusions, and ascites. Infants with HDN caused by RhD and some minor blood groups (eg, Kell), are at risk for hydrops fetalis, especially pregnancies without antenatal care. ABO HDN is generally less severe than that caused by the Rh and Kell systems; however, there are rare case reports of hydrops fetalis due to ABO incompatibility [4]. Because of the rare incidence of hydrops fetalis in neonates with ABO incompatibility, other causes for the severe hemolysis should be sought in these cases. (See 'Differential diagnosis' below.)

Neonates with hydrops fetalis may present at delivery with shock or near shock and require emergent transfusion. (See 'Early life-threatening anemia (hydrops fetalis)' below.)

ANTENATAL DIAGNOSIS — Antenatal diagnosis and management of alloimmune hemolytic disease in the fetus are discussed separately. (See "RhD alloimmunization in pregnancy: Overview" and "Management of non-RhD red blood cell alloantibodies during pregnancy".)

POSTNATAL EVALUATION AND DIAGNOSIS

Evaluation

Whom to test — We suggest evaluating for HDN if:

The mother’s antibody screen is positive or unknown, or

The neonate has clinical signs of HDN (eg, onset of jaundice within 24 hours after birth, symptomatic anemia), particularly in a newborn born to a type O mother

It is not necessary to perform testing on every newborn born to a type O mother, provided the mother’s antibody screen is negative and the infant undergoes routine bilirubin screening during the birth hospitalization. If the neonate’s bilirubin level is not concerning, further evaluation is generally not necessary. Newborns who develop clinically significant hyperbilirubinemia require additional testing [19]. (See 'Tests to perform' below and "Unconjugated hyperbilirubinemia in term and late preterm newborns: Screening", section on 'Additional laboratory evaluation'.)

Tests to perform — Initial tests to perform in newborns with suspected HDN include all of the following:

Maternal and infant blood type (ABO and RhD) and maternal antibody screen – Maternal blood type testing and antibody screening is routinely performed prenatally. Infant blood type testing can be performed on cord blood sent from the delivery room or from a blood sample collected from the newborn. (See "Prenatal care: Second and third trimesters", section on 'Screen for red blood cell antibodies and administer anti-D immune globulin to D-negative patients' and "Labor and delivery: Management of the normal third stage after vaginal birth", section on 'Cord blood'.)

Bilirubin level – Many birthing centers routinely perform bilirubin screening in all newborns prior to discharge. In newborns with clinical concern for HDN (eg, onset of jaundice within 24 hours after birth), the bilirubin level should be measured earlier than the routine predischarge screen. (See "Unconjugated hyperbilirubinemia in term and late preterm newborns: Screening", section on 'Timing of screening'.)

Bilirubin levels can be measured with either (see "Unconjugated hyperbilirubinemia in term and late preterm newborns: Screening", section on 'Bilirubin testing methods'):

Blood tests that directly measure the total serum or plasma bilirubin (TSB) level.

Noninvasive methods that estimate bilirubin levels (ie, transcutaneous bilirubin [TcB]) or assess for hemolysis (ie, end-tidal carbon monoxide). Abnormal values based on noninvasive measures should generally be confirmed with TSB. (See "Unconjugated hyperbilirubinemia in term and late preterm newborns: Screening", section on 'Transcutaneous bilirubin (TcB)' and "Unconjugated hyperbilirubinemia in term and late preterm newborns: Screening", section on 'Testing for hemolysis'.)

Direct antiglobulin test (DAT; formerly called Coombs test) – The DAT can be performed on cord blood sent from the delivery room or from a blood sample collected from the newborn. However, a false positive DAT may occur due to contamination of the cord blood sample with Wharton's jelly [20,21]. If DAT is negative but clinical suspicion for HDN remains high, an indirect antiglobulin test (IAT) should be performed.

Complete blood count (CBC) and peripheral blood smear.

Reticulocyte count, which is a helpful marker for assessing the presence and severity of hemolysis.

Cross match (only if transfusion is needed).

Interpretation of the DAT — In the DAT, agglutination of red blood cells (RBCs) from the neonate, when suspended with serum that contains antibodies to immunoglobulin G (IgG), indicates the presence of maternal antibody on the RBC surface.

Positive DAT – A positive DAT demonstrates the presence of maternal antibody on the neonate's RBCs and is consistent with HDN. (See 'Diagnosis' below.)

Negative DAT – A negative DAT does not exclude the diagnosis of HDN, particularly in the setting of ABO incompatibility. This is because the A and B antigens are less well developed in neonates than in older children and adults, and thus the DAT may not detect sensitized RBCs. In addition, the antigenic sites are fewer and farther apart on neonatal RBCs, making agglutination with the reagent more difficult [11].

If the DAT is negative, an elution is performed on the infant's RBCs to free any bound maternal antibodies into the serum, then an indirect antiglobulin test (IAT) is performed with the eluted serum. In IAT, RBCs with a specific antigen, such as RhD, A, or B, are incubated with the infant's serum. Antibodies to the specific antigen will adhere to the RBCs. The RBCs are then washed and suspended in serum containing antihuman globulin. A positive IAT is indicated by agglutination of RBCs coated with maternal antibody, demonstrating the presence of free maternal antibodies in the neonatal serum [22]. However, a positive IAT only confirms that maternal antibodies have crossed into the neonate's circulation. Thus, it is a supportive finding but is not diagnostic of HDN.

Infants with Rh HDN who have received intrauterine transfusions may also have a negative DAT because the presence of donor Rh-negative RBCs makes agglutination more difficult. In these cases, the IAT will remain strongly positive. However, neonates managed with intrauterine transfusion generally already have an established antenatal diagnosis of HDN, and thus it is generally not necessary to confirm the diagnosis postnatally.

Negative DAT and IAT – In infants with suspected HDN with both negative DAT and IAT, other causes for hyperbilirubinemia should be sought (eg, glucose-6-phosphate dehydrogenase [G6PD] deficiency, hereditary spherocytosis, Gilbert syndrome). (See 'Differential diagnosis' below and "Unconjugated hyperbilirubinemia in neonates: Etiology and pathogenesis", section on 'Causes of significant unconjugated neonatal hyperbilirubinemia'.)

Diagnosis — The diagnosis of HDN is confirmed when all three of the following criteria are fulfilled:

Demonstration of incompatible blood types between the infant and mother. The most common incompatibilities are:

Rhesus D (RhD)-positive infant born to an RhD-negative mother (see 'RhD hemolytic disease' above)

Group A or B blood type in an infant born to a mother with group O blood type (see 'ABO hemolytic disease' above)

Incompatibilities in other minor blood groups such as Kell, Duffy, MNS, P, and others (table 1) (see 'Other blood group antibodies' above)

Laboratory evidence of hemolysis (any of the following):

Unconjugated hyperbilirubinemia, especially if present during the first 24 hours of life.

Anemia with elevated reticulocyte count – The normal absolute reticulocyte count in cord blood of term infants is 137.3±33 x 109 L, which corresponds to a reticulocyte fraction of 3.1±0.75 percent [23].

Peripheral blood smear findings consistent with hemolysis, including decreased number of RBCs, reticulocytosis, macrocytosis, and polychromasia. Spherocytosis or microspherocytosis (due to partial membrane loss) is commonly seen in infants with ABO alloimmune HDN, but it is generally not seen in infants with Rh disease.

A positive DAT, indicating antibody-mediated hemolysis. If the DAT is negative but other diagnostic criteria are met, a positive IAT supports the diagnosis of HDN.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis for HDN includes other causes of neonatal jaundice and hemolytic anemia. HDN is differentiated from the following disorders by the presence of a positive direct or indirect antiglobulin test (DAT/IAT; Coombs test). It is important to recognize that a newborn can have more than one cause of jaundice. If another disorder occurs concomitantly with HDN, the hyperbilirubinemia may be particularly severe [24,25].

The differential diagnosis of unconjugated hyperbilirubinemia and/or hemolytic anemia during the neonatal period includes the following disorders. Other causes of unconjugated hyperbilirubinemia and/or hemolytic anemia are discussed in separate topic reviews (see "Unconjugated hyperbilirubinemia in neonates: Etiology and pathogenesis" and "Overview of hemolytic anemias in children"):

Erythrocyte membrane defects – The peripheral blood smear and the negative antiglobulin tests distinguish the inherited erythrocyte membrane defects, such as hereditary spherocytosis [26] (picture 1) or elliptocytosis (picture 2), from HDN [27]. (See "Hereditary spherocytosis" and "Hereditary elliptocytosis and related disorders".)

Erythrocyte enzyme defects – Enzyme assays confirm the diagnosis of erythrocyte enzyme defects, such as glucose-6-phosphate dehydrogenase (G6PD) or pyruvate kinase deficiencies. For patients with G6PD deficiency, the peripheral blood smear reveals microspherocytes, eccentrocytes or "bite cells," and "blister cells" with hemoglobin puddled to one side (picture 3). (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency".)

Gilbert syndrome – Gilbert syndrome is the most common inherited disorder of bilirubin glucuronidation. It results from a mutation in the promoter region of the UGT1A1 gene, causing a reduced production of UGT, which leads to unconjugated hyperbilirubinemia. A normal hematocrit, reticulocyte count, and peripheral blood smear distinguish this disorder from HDN. (See "Unconjugated hyperbilirubinemia in neonates: Etiology and pathogenesis", section on 'Gilbert syndrome'.)

ANTENATAL MANAGEMENT — In developed countries, routine antenatal care includes screening for maternal antibodies that can potentially cause HDN. If such antibodies are detected, management is directed toward monitoring maternal antibody titers and the status of the fetus (ie, fetal anemia). Fetal red blood cell (RBC) transfusions are sometimes necessary. Antenatal care and the prevention of maternal Rhesus (Rh) sensitization have significantly reduced the number of infants born with severe manifestations of HDN. Antenatal management is discussed in greater detail separately. (See "RhD alloimmunization: Prevention in pregnant and postpartum patients" and "RhD alloimmunization in pregnancy: Overview" and "Management of non-RhD red blood cell alloantibodies during pregnancy" and "Intrauterine fetal transfusion of red blood cells".)

POSTNATAL MANAGEMENT — Postnatal management for affected infants is focused on treating the anemia and hyperbilirubinemia caused by hemolysis. The duration of the anemia in infants with HDN depends on the severity of the anemia at presentation and the timing of onset (early versus late type).

Management approach

Delivery room management

Anticipating the newborn's needs – Infants with Rhesus D (RhD) and some minor blood group incompatibilities (eg, Kell) are at risk for hydrops fetalis. The status of a newborn with HDN due to Rh or Kell incompatibility cannot be predicted with certainty at the time of delivery, even if antenatal care has been provided. As a result, delivery room management should anticipate the needs of the most severely affected infant, including the ability to promptly transfuse group O, RhD-negative red blood cells (RBCs) in neonates with severe life-threatening anemia. (See 'Hydrops fetalis' above and "Nonimmune hydrops fetalis in the neonate: Causes, presentation, and overview of neonatal management", section on 'Overview of initial neonatal management'.)

Delayed cord clamping – For vigorous term and preterm newborns, delaying cord clamping for at least 30 to 60 seconds has been shown to be beneficial; the impact in newborns with HDN is likely even greater than for the general newborn population. The evidence supporting delayed cord clamping is discussed separately. (See "Labor and delivery: Management of the normal third stage after vaginal birth", section on 'Early versus delayed cord clamping'.)

In one observational study limited to newborns with HDN, delayed cord clamping was associated with a lower incidence of anemia and reduced need for exchange transfusion [28].

Assessment of the newborn – At delivery, assessment includes evaluation of the infant's respiratory and cardiovascular systems, and the severity of hemolysis. Pallor, tachycardia, and tachypnea are findings suggestive of symptomatic anemia. Respiratory distress may also be due to pleural effusions or pulmonary hypoplasia in infants with hydrops fetalis.

Laboratory evaluation – In all cases, if HDN is suspected or known at the time of delivery, cord blood should be sent for the following tests [29] (see 'Tests to perform' above):

Hematocrit, reticulocyte count, and bilirubin concentration to guide decisions on therapeutic interventions (eg, transfusions and/or phototherapy)

Blood type and direct antiglobulin test (DAT; previously called Coombs test) to confirm the diagnosis

Cross match in the event that transfusion is required

Early life-threatening anemia (hydrops fetalis) — Neonates with life-threatening, severe anemia (hydrops fetalis) may present at delivery with shock or near shock. In these patients, management includes the following:

At delivery, which may occur in the delivery room or operating room (cesarean delivery), emergency transfusion with group O, RhD-negative RBCs is required to stabilize the neonate [30]. The initial volume administered is 10 mL/kg because these neonates are already fluid overloaded and may not tolerate larger volumes. Thoracentesis or paracentesis may be required in infants with significant respiratory distress due to pleural effusions and/or ascites [31]. (See "Neonatal resuscitation in the delivery room", section on 'Volume expansion' and "Nonimmune hydrops fetalis in the neonate: Causes, presentation, and overview of neonatal management", section on 'Delivery room care'.)

After stabilization, early exchange transfusion is typically performed in the neonatal intensive care unit (NICU) to reduce hemolysis and correct anemia [31]. (See 'Early non-life-threatening disease' below.)

Early non-life-threatening disease — Management is based upon the severity of anemia and hyperbilirubinemia:

Severe anemia and/or severe hyperbilirubinemia – For patients with severe anemia (hematocrit <25 percent) and/or severe hyperbilirubinemia (ie, bilirubin at or above the hour-specific threshold for exchange transfusion as established in the American Academy of Pediatrics [AAP] guidelines (figure 1)), exchange transfusion is preferred over simple transfusion because it not only corrects anemia but also reduces hemolysis by replacing antibody-coated neonatal RBCs with donor RBCs, which do not have the sensitizing antigen, and removes a portion of the unbound maternal antibody. (See 'Exchange transfusion' below.)

The AAP thresholds for exchange transfusions and a description of the procedure itself, including its risks, are discussed in detail separately. (See "Unconjugated hyperbilirubinemia in term and late preterm newborns: Escalation of care", section on 'Exchange transfusion'.)

Early exchange transfusion requires skilled personnel to be available to perform the procedure. If there is a delay or inability to perform an exchange transfusion, simple RBC transfusion may be used, recognizing that repeat transfusions may be necessary because of ongoing hemolysis. In addition, treatment with intravenous immune globulin (IVIG) can be considered if exchange transfusion is not readily available since IVIG may reduce the need for exchange transfusion, especially in infants with ABO hemolytic disease. (See 'Immune globulin therapy' below.)

Moderate anemia and nonsevere hyperbilirubinemia – For patients with moderate to severe anemia (hematocrit between 25 and 35 percent) and nonsevere hyperbilirubinemia (ie, below the threshold for exchange transfusion), we suggest simple transfusion.

Hyperbilirubinemia due to HDN is managed in the same manner as for neonatal unconjugated hyperbilirubinemia more broadly. The mainstays of management include serial monitoring of total serum bilirubin (TSB) levels, oral hydration, and phototherapy. We follow the AAP guidelines for the initiation and discontinuation of phototherapy based upon hour-specific TSB values and gestational age (figure 2) [19]. Since HDN is one of five key risk factors for bilirubin-induced neurotoxicity (table 2), a lower threshold is used for starting phototherapy in newborns with HDN compared with those without neurotoxicity risk factors. The AAP guidelines are discussed in greater detail separately. (See "Unconjugated hyperbilirubinemia in term and late preterm newborns: Initial management".)

For infants who do not respond to these conventional measures, additional interventions may include:

IV hydration – Most newborns with hyperbilirubinemia do not require IV hydration. However, IV hydration may be needed if oral intake is inadequate or if the newborn requires escalation of care for hyperbilirubinemia (ie, if the TSB is approaching the threshold for exchange transfusion). (See "Unconjugated hyperbilirubinemia in term and late preterm newborns: Escalation of care", section on 'IV hydration'.)

IVIG – We suggest IVIG in infants with HDN if the TSB is rising despite intensive phototherapy or is within 2 mg/dL (34 micromol/L) of the threshold for exchange transfusion. (See 'Immune globulin therapy' below.)

Exchange transfusion – In our practice, we perform an exchange transfusion if the TSB persists above the threshold values outlined by the AAP guidelines after a trial of phototherapy, IVIG, and IV hydration (figure 1 and algorithm 1). In addition, immediate exchange transfusion is recommended if the infant demonstrates signs of acute bilirubin encephalopathy (table 3). (See 'Exchange transfusion' below.)

Of note, ABO incompatibility does not typically result in severe hemolysis and/or extreme hyperbilirubinemia. Thus, newborns with confirmed ABO hemolytic disease who have persistently elevated bilirubin concentrations despite standard therapeutic interventions should undergo evaluation for other causes of hyperbilirubinemia [32-34]. Some newborns may have additional contributing factors (eg, inherited hemolytic disorders) that interact synergistically, resulting in extremely high bilirubin concentrations and even acute bilirubin encephalopathy [35]. (See 'Differential diagnosis' above and "Unconjugated hyperbilirubinemia in neonates: Etiology and pathogenesis", section on 'Causes of significant unconjugated neonatal hyperbilirubinemia'.)

Mild anemia and nonsevere hyperbilirubinemia – Patients with hematocrit >35 percent generally do not require transfusion. The management of hyperbilirubinemia in this setting is the same as for neonatal unconjugated hyperbilirubinemia more broadly. This is described separately. (See "Unconjugated hyperbilirubinemia in term and late preterm newborns: Initial management".)

These patients are at risk for late anemia, and it may be reasonable to treat with an erythropoiesis stimulating agent (ESA), such as epoetin alfa or its longer-acting analogue darbepoetin. The rationale is that this may avoid subsequent transfusion. The indications for and efficacy of ESAs in this setting have not been established. In our practice, we use ESAs in the following circumstances:

Infants with Rh, ABO, or Kell incompatibility with progressive anemia but not yet at a level to warrant transfusion

Neonates with HDN born to families whose religious tradition prohibits transfusion

In our center, we typically use darbepoetin for this purpose since it requires fewer injections. Infants treated with ESAs should receive concomitant iron supplementation. (See 'Late anemia' below and 'Erythropoiesis stimulating agents' below.)

Late anemia

Presentation – Late-onset anemia presenting one to three weeks after birth may be seen in the following settings:

Neonates with ABO [36], minor blood groups (eg, Gerbich [37] and Kell system [38]), and Rh [39] incompatibilities. In these neonates, late-onset anemia may be due to immune destruction of erythroid progenitors [37].

Neonates who received intrauterine transfusions, in whom hemolytic anemia may be delayed until the transfused RBCs are replaced with the neonate's own RBCs (which express the alloimmune antigen and, therefore, are vulnerable to persistent maternal antibody-mediated hemolysis).

Neonates who initially had mild anemia from HDN, which is subsequently accentuated by the suppression of erythropoiesis, which normally occurs for all neonates at three to four weeks of age.

Prevention – As previously discussed, ESAs have been used in at-risk neonates to prevent late-onset anemia and avoid the need for transfusion. (See 'Early non-life-threatening disease' above and 'Erythropoiesis stimulating agents' below.)

Treatment – Treatment options for late-onset anemia are as follows:

Asymptomatic infants are treated with iron supplementation (3 to 6 mg/kg/day enterally, depending on amount of enteral feeds), and phlebotomy is minimized to reduce further blood loss [40]. (See "Iron deficiency in infants and children <12 years: Treatment".)

Infants with symptomatic late-onset anemia are generally treated with simple transfusion. (See 'Simple transfusion' below.)

Breastfeeding — Although maternal antibodies are present in breast milk, very little antibody is absorbed [41]. Thus, mothers should be encouraged to breastfeed without restrictions. (See "Initiation of breastfeeding".)

Ongoing monitoring — Infants with HDN require continued ongoing monitoring until their bilirubin concentrations are in a safe range and trending down, without ongoing treatment.

The duration of illness is variable in infants with HDN and depends on the following factors:

Since there is considerable variation in the strength of the reactivity of the various antigens involved in HDN, the degree of initial hemolysis is also variable. Maternal antibody levels are not useful to predict the hemolytic process because they are poorly correlated with the degree of hemolysis [42].

Treatment results in variable duration of elevated bilirubin levels (which are not predictable). Exchange transfusion and the administration of IVIG can result in dramatic improvements in reducing the rate of hemolysis, which reduces ongoing bilirubin production.

Infants with late anemia caused by Rh disease should be monitored until the reticulocyte count recovers, which may take weeks to months, depending on the severity of the anemia and the chosen treatment. It is important to note that physiologic anemia occurs during this same time period (8 to 12 weeks after delivery). Neonates with HDN who have hemoglobin/hematocrits below the normal range prior to the physiologic nadir should be monitored closely as they are at risk for an exaggerated physiologic anemia.

Interventions — The following sections provide additional details regarding the interventions used to treat HDN. The approach to selecting among these interventions according to the severity of disease is reviewed above. (See 'Management approach' above.)

Phototherapy — Phototherapy is the most commonly used intervention to treat and prevent severe hyperbilirubinemia. It is an effective and safe intervention. The AAP has developed hour-specific thresholds for initiating phototherapy based upon TSB levels and gestational age (figure 2) (calculator 1). Since HDN is one of five key risk factors for bilirubin-induced neurotoxicity (table 2), a lower threshold is used for starting phototherapy in newborns with HDN compared with those without neurotoxicity risk factors. Additional details are provided separately. (See "Unconjugated hyperbilirubinemia in term and late preterm newborns: Initial management", section on 'Initial intervention (phototherapy)'.)

In newborns with ABO incompatibility, early transcutaneous bilirubin (TcB) levels may predict the need for early phototherapy. In one study, newborns with TcB value ≥5.3 mg/dL at six hours after birth were most likely to require phototherapy within the first 24 hours after birth, whereas newborns with TcB values <3 mg/dL at six hours after birth were unlikely to require early phototherapy [43]. (See "Unconjugated hyperbilirubinemia in term and late preterm newborns: Screening", section on 'Transcutaneous bilirubin (TcB)'.)

Transfusion

Simple transfusion — Simple RBC transfusion may be required in patients with anemia that is moderate to severe (hematocrit between 25 and 35 percent and/or symptoms attributable to anemia) without severe hyperbilirubinemia (ie, not requiring exchange transfusion (figure 1)). In addition, simple transfusion may be used in infants with more severe anemia and/or hyperbilirubinemia if exchange transfusion is not readily available.

RBC transfusions generally are given in aliquots of 10 to 20 mL/kg, over two to four hours. Selection of blood products for transfusion is summarized in a table and is discussed below (table 4). (See 'Selection of blood product' below.)

Additional details regarding RBC transfusions in neonates are provided separately. (See "Red blood cell (RBC) transfusions in the neonate".)

Exchange transfusion — Exchange transfusion is used to treat severe anemia and severe hyperbilirubinemia. Exchange transfusion removes serum bilirubin and decreases hemolysis by the removal of antibody-coated neonatal RBCs and unbound maternal antibody.

Immediate exchange transfusion is recommended if the infant has hyperbilirubinemia associated with clinical signs of acute bilirubin encephalopathy, such as lethargy, hyper- or hypotonia, poor suck, high-pitched cry, recurrent apnea, opisthotonos, retrocollis, or seizures (table 3). (See "Unconjugated hyperbilirubinemia in term and late preterm newborns: Escalation of care", section on 'Exchange transfusion' and "Unconjugated hyperbilirubinemia in neonates: Risk factors, clinical manifestations, and neurologic complications", section on 'Acute bilirubin encephalopathy (ABE)'.)

The optimal threshold for initiating exchange transfusion in infants with HDN to prevent encephalopathy is unknown [31]. In our practice, we perform an exchange transfusion if the TSB persists above the threshold values outlined by the AAP guidelines after a trial of phototherapy, IVIG, and IV hydration (figure 1). An alternative method uses a rise of TSB >0.5 mg/dL (8 mmol/L) per hour, despite intensive phototherapy, as an indication for exchange transfusion [31,44]. Some experts have suggested a cord bilirubin level >4.5 mg/dL (77 mmol/L) as an initial threshold for exchange transfusion based upon clinical practice [45]. However, cord bilirubin levels do not appear to accurately predict postnatal TSB levels in neonates with HDN [44].

With prenatal diagnosis and management and the use of IVIG, few infants managed in the modern era require exchange transfusions. Selection of blood products for transfusion is summarized in a table (table 4) and is discussed below. (See 'Selection of blood product' below.)

Additional details regarding exchange transfusion are provided separately.

Selection of blood product — The following bullet points outline selection of an appropriate RBC product according to the type of HDN (table 4). All neonatal RBC transfusions are performed with irradiated cytomegalovirus-safe products. (See "Red blood cell (RBC) transfusions in the neonate", section on 'Cytomegalovirus-safe RBCs for all neonates' and "Red blood cell (RBC) transfusions in the neonate", section on 'Indications for irradiated RBCs'.)

RhD disease – A newborn who needs either simple or exchange transfusion in the setting of RhD disease should receive RhD-negative, ABO-matched RBCs. Some institutions may use group O, RhD-negative RBCs for all neonatal transfusions, in which case the RBCs are washed to remove any alloantibodies to group A or B antigens in the plasma.

ABO incompatibility – For newborns with HDN due to ABO incompatibility, group O RBCs are used. Donor O RBCs are washed to remove any plasma-containing alloantibodies. For exchange transfusion, washed RBCs are suspended in fresh frozen plasma that is compatible with both the infant's RBCs and the transfused (donor) RBCs. Plasma from an AB donor is compatible in all cases, since it does not contain anti-A or anti-B alloantibodies.

Other Rh antibodies – For newborns with HDN due to other antibodies (eg, Rh antibodies in the C and E systems, and Kell antibodies), transfusions are performed with RBCs that are negative for the specific antigen.

Immune globulin therapy — The proposed mechanism for IVIG in treating HDN is inhibition of hemolysis by blocking antibody receptors on RBCs.

Indications – We suggest IVIG in neonates with HDN if the TSB is rising despite intensive phototherapy or is within 2 mg/dL (34 micromol/L) of the threshold for exchange transfusion (figure 1) [19].

Dosing – The recommended dose is 500 to 1000 mg/kg given over two hours. The dose may be repeated in 12 hours if necessary.

Efficacy – The efficacy of IVIG in this setting is supported by clinical trials with important limitations that demonstrated reduced need for exchange transfusion in neonates treated with IVIG [46-49].

Rh HDN – In a meta-analysis of nine trials involving 426 neonates with Rh HDN, IVIG reduced the need for exchange transfusion (risk ratio [RR] 0.43; 95% CI 0.25-0.74) [50]. However, many of the trials in the meta-analysis had important methodologic limitations (eg, lack of blinding, incomplete follow-up, selective reporting), and results were inconsistent between trials. In a subgroup analysis limited to the three trials (n = 190 neonates) that were deemed to be of high methodologic quality, the reduction in need for exchange transfusion was less dramatic, and the difference was not statistically significant (RR 0.82, 95% CI 0.53-1.26).

ABO HDN – In a separate meta-analysis of five trials involving 350 neonates with ABO HDN, IVIG reduced the need for exchange transfusion (RR 0.31, 95% CI 0.18-0.55); however, all five trials had important methodologic limitations, and thus the certainty in this finding is low [50].

Other blood groups – Data are limited on use of IVIG in other blood group incompatibilities, such as anti-C and anti-E disease [51,52].

Adverse effects – Adverse effects of IVIG include fever, allergic reactions, fluid overload, and rebound hemolysis [53]. (See "Overview of intravenous immune globulin (IVIG) therapy", section on 'Adverse effects'.)

There were no IVIG-related safety concerns reported in the randomized trials discussed above. However, observational studies have reported an association between IVIG and necrotizing enterocolitis [49,54,55].

Erythropoiesis stimulating agents — ESAs, including recombinant human erythropoietin (epoetin alfa) and its longer-acting analog darbepoetin, are sometimes used in selected infants in an effort to reduce or prevent the need for transfusion [56,57]. This includes infants with Kell, Rh, or ABO incompatibility with progressive anemia but not yet at a level to require transfusion, or families whose religious tradition prohibits transfusion.

Dosing for ESAs is as follows:

Epoetin is given subcutaneously at a dose of 400 units/kg three times weekly for two weeks [40].

Darbepoetin is given subcutaneously as a one-time dose of 10 mcg/kg. If needed, the dose may be repeated after one to two weeks.

Longer courses of ESAs have also been used [38].

In our center, we preferentially use darbepoetin because it requires fewer injections (usually a single injection versus three to five injections over two weeks for epoetin).

Infants receiving ESAs should also generally be treated with supplemental iron (6 mg/kg of elemental iron per day). It is uncertain whether iron supplementation is necessary in newborns treated with intrauterine transfusion since stores are usually high in these patients.

Of note, ESA therapy requires time to have an effect; a rise in hematocrit usually is not seen for at least five days [40]. Additional details regarding use of these agents in preterm neonates are provided separately. (See "Anemia of prematurity (AOP)", section on 'Erythropoiesis stimulating agents (ESAs)'.)

Metalloporphyrins — Synthetic metalloporphyrins have been studied as potential therapeutic and preventative agents in the management of hyperbilirubinemia in the neonate. However, data are limited and inconclusive regarding efficacy, and they are not available for routine use anywhere in the world. (See "Unconjugated hyperbilirubinemia in term and late preterm newborns: Initial management", section on 'Unproven therapies'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Rh disease in pregnancy".)

SUMMARY AND RECOMMENDATIONS

Types of HDN – Alloimmune hemolytic disease of the newborn (HDN), is caused by the destruction of fetal or neonatal red blood cells (RBCs) due to maternal antibodies. These antibodies are produced when an RBC antigen not expressed in the mother, gains access to the maternal circulation, either from a gestating fetus or exogenous source (transfusion).

HDN primarily involves the major blood groups of Rhesus (Rh), A, B, AB, and O, although minor blood group incompatibilities (eg, Kell, Duffy, and others) can also result in significant disease (table 1). (See 'Types of HDN' above.)

Clinical presentation – Clinical manifestations of HDN range from mild, self-limited hemolytic disease to severe, life-threatening anemia (eg, hydrops fetalis). Infants with ABO HDN generally have less severe disease than those with Rh hemolytic disease. (See 'Clinical presentation' above.)

Hydrops fetalis – Infants with severe, life-threatening anemia may present with hydrops fetalis, manifested by diffuse edema, pleural and/or pericardial effusions, and ascites. This presentation occurs predominantly in infants with RhD and some minor blood group incompatibilities (eg, Kell). (See 'Hydrops fetalis' above.)

Less severe presentation – Less severely affected infants typically present with hyperbilirubinemia within the first 24 hours after birth and/or symptomatic anemia (eg, lethargy or tachycardia). (See 'Mild to moderate disease' above.)

Evaluation – Initial tests to perform in newborns with suspected HDN include (see 'Evaluation' above):

Maternal and infant blood type and maternal antibody screen

Direct antiglobulin test (DAT)

Bilirubin level

Complete blood count (CBC) and peripheral blood smear

Reticulocyte count

Diagnosis – The diagnosis of HDN is confirmed when all of the following criteria are fulfilled (see 'Diagnosis' above):

Demonstration of incompatible blood types between the infant and mother

Laboratory evidence of hemolysis (eg, unconjugated hyperbilirubinemia, anemia with elevated reticulocyte count, and/or peripheral blood smear findings consistent with hemolysis)

Positive DAT (if the DAT is negative but other diagnostic criteria are met, a positive indirect antiglobulin test [IAT] supports the diagnosis of HDN)

Differential diagnosis – The differential diagnosis for HDN includes other causes of neonatal jaundice and/or hemolytic anemia. Alloimmune HDN is differentiated from these disorders by the presence of a positive DAT and/or IAT. (See 'Differential diagnosis' above.)

Management – The postnatal management for HDN is dependent on both the severity of anemia and hyperbilirubinemia (see 'Postnatal management' above):

Early life-threatening anemia (hydrops fetalis) – Infants with life-threatening anemia (hydrops fetalis) require emergency transfusion using group O, RhD-negative RBCs. (See 'Early life-threatening anemia (hydrops fetalis)' above and 'Transfusion' above.)

Early severe anemia and/or severe hyperbilirubinemia – For patients with early severe symptomatic anemia (hematocrit <25 percent) and/or severe hyperbilirubinemia (based upon hour-specific bilirubin values (figure 1) (calculator 1)), we suggest exchange transfusion rather than simple transfusion (Grade 2C). However, if there is a delay or inability to perform exchange transfusion, simple RBC transfusion and treatment with intravenous immune globulin (IVIG) are reasonable options. (See 'Early non-life-threatening disease' above and 'Exchange transfusion' above and 'Immune globulin therapy' above.)

Moderate to severe anemia and nonsevere hyperbilirubinemia – For patients with moderate to severe anemia (hematocrit between 25 and 35 percent) and nonsevere hyperbilirubinemia (ie, not requiring exchange transfusion), we suggest simple transfusion (Grade 2C). Selection of RBCs for transfusion depends on the type of HDN (table 4). (See 'Transfusion' above.)

Hyperbilirubinemia due to HDN is generally managed in the same manner as for neonatal unconjugated hyperbilirubinemia more broadly. The mainstays of management include serial monitoring of serum bilirubin levels, oral hydration, and phototherapy. Thresholds for starting phototherapy are summarized in the figure (figure 2). Additional details are provided separately. (See "Unconjugated hyperbilirubinemia in term and late preterm newborns: Initial management".)

For neonates with rising bilirubin levels despite intensive phototherapy or with levels that are within 2 mg/dL (34 micromol/L) of the threshold for exchange transfusion (figure 1), we suggest IVIG (Grade 2C). The usual dose is 500 to 1000 mg/kg given over two hours. (See 'Immune globulin therapy' above.)

Mild anemia and nonsevere hyperbilirubinemia – Patients with hematocrit >35 percent generally do not require transfusion. Management of these newborns focuses on monitoring and treating hyperbilirubinemia, as discussed separately. (See "Unconjugated hyperbilirubinemia in term and late preterm newborns: Initial management".)

In addition, infants who initially have mild anemia are at risk for late-onset anemia, presenting one to three weeks after birth. For infants with Rh, ABO, or Kell incompatibility who have progressive anemia not yet at a level to warrant transfusion, we suggest administering an erythropoietic stimulating agent (ESA) (Grade 2C). The rationale is that this may prevent subsequent need for transfusion. We typically use a single dose of darbepoetin (10 mcg/kg given subcutaneously) in this setting. Iron supplementation should be provided in conjunction with ESA therapy. (See 'Late anemia' above and 'Erythropoiesis stimulating agents' above.)

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References

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