INTRODUCTION — Hemolytic disease of the fetus and newborn (HDFN), also known as alloimmune HDFN or erythroblastosis fetalis, 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 fetal erythrocytes, which express an RBC antigen not expressed in the mother, gain access to the maternal circulation.

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

TYPES OF HDFN — Alloimmune HDFN 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]. Because of the low frequency of HDFN due to the minor blood groups, they are not presented in detail as part of this review. (See "Red blood cell antigens and antibodies".)

Only maternal immunoglobulin G (IgG) causes HDFN, 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 HDFN 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 an Rh-positive offspring. Thus, in the absence of transfusion, Rh HDFN 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 HDFN range from mild, self-limited hemolytic disease to severe life-threatening anemia (eg, hydrops fetalis). The severity of HDFN 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 — Humans have four major blood groups 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 (found ubiquitously in food and bacteria) they do not possess. As a result, ABO HDFN can occur with the first pregnancy and occurs almost exclusively in mothers with blood type O [2,3].

Although ABO incompatibility occurs in approximately 15 percent of all pregnancies, it results in neonatal hemolytic disease in only 4 percent of such pregnancies (ie, 0.6 percent of all pregnancies). ABO hemolytic disease is more common and severe in infants of African descent [4]. Infants with ABO HDFN generally have less severe disease than those with RhD incompatibility. Affected infants 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 HDFN [1]. Hydrops fetalis is rare, and clinically significant hemolysis is uncommon, as less than 0.1 percent of infants with evidence of hemolysis will require exchange transfusions [4,5].

As a result, other additional causes for the jaundice should be sought for neonates with ABO incompatibility who have a severe hemolytic condition that results in hydrops/erythroblastosis fetalis, readmission for jaundice, a total serum bilirubin (TSB) ≥25 mg/dL, or kernicterus. (See 'Differential diagnosis' below.)

With the advent of universal screening for hyperbilirubinemia and management programs, it was observed that neonates with blood groups A and B were not more likely to develop TSB ≥25 mg/dL than group O neonates born to group O and RhD-positive women [6]. It has been proposed the absence of more severe clinical disease in neonates with blood groups A or B with direct antiglobulin test (DAT)-positive A or B neonates is due to the paucity of A and B antigenic sites on the neonatal RBC [7]. This observation has led to a suggestion that the routine blood typing and testing for every infant born to a mother with blood group O at centers with universal screening may not be necessary [6].

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 HDFN and include Duffy, MNS, and P (table 1). 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. There are also racial differences in blood group antigen distribution [8]. (See "Management of non-RhD red blood cell alloantibodies during pregnancy".)

Although RhD incompatibility remains the most frequent cause of Rh HDFN, some of the other more than 44 Rh antigens, particularly E and C, have been associated with HDFN (table 1) [9]. (See "Red blood cell antigens and antibodies", section on 'Rh blood group system'.)

The clinical disease associated with HDFN 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 HDFN can be severe and may require intrauterine intervention. (See "Management of non-RhD red blood cell alloantibodies during pregnancy".)

CLINICAL PRESENTATION — Clinical manifestations of HDFN 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 — Less severely affected infants typically present with self-limited hemolytic disease, manifested as hyperbilirubinemia within the first 24 hours of life. They may also have symptomatic anemia (eg, lethargy or tachycardia) but without signs of circulatory collapse. The degree of anemia varies depending upon the type of HDFN. Infants with ABO incompatibility 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 Rhesus (Rh) or some minor blood group incompatibilities can present with symptomatic anemia that requires red blood cell (RBC) transfusion. (See 'Early anemia' below.)

Hydrops fetalis — Infants with severe life-threatening anemia (eg, hydrops fetalis) present with skin edema, pleural or pericardial effusion, or ascites. Infants with RhD and some minor blood group incompatibilities, such as Kell, are at risk for hydrops fetalis, especially pregnancies without antenatal care. ABO HDFN is generally less severe than that caused by the Rh and Kell systems; however, there are case reports of hydrops fetalis due to ABO incompatibility [4]. Because of the lower severity of hydrops fetalis in neonates with ABO incompatibility, other causes for the severe hemolysis should be sought (see 'Differential diagnosis' below). Neonates with hydrops fetalis may present at delivery with shock or near shock and require emergent transfusion. (See 'Life-threatening severe anemia (hydrops fetalis)' below.)

DIAGNOSIS

Antenatal diagnosis — The antenatal diagnosis and management of HDFN are discussed separately. (See "RhD alloimmunization in pregnancy: Overview" and "Management of non-RhD red blood cell alloantibodies during pregnancy".)

Postnatal diagnosis — HDFN is clinically suspected when the following two major criteria are fulfilled when a diagnosis has not been made antenatally:

●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)

●Demonstration of hemolysis by one or the following measures:

•Peripheral blood smear findings consistent with HDFN include decreased number of red blood cells (RBCs), reticulocytosis, macrocytosis, and polychromasia.

•Increased 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 [10].

•Microspherocytosis (due to partial membrane loss) or spherocytosis is commonly seen in the peripheral smear of infants with ABO alloimmune HDFN, but it is generally not seen in infants with Rh disease.

•Indirect hyperbilirubinemia, especially during the first 24 hours of life.

•Evidence of hemolysis based on elevated end-tidal carbon monoxide [7]. (See "Unconjugated hyperbilirubinemia in term and late preterm infants: Screening", section on 'Additional tests'.)

The postnatal diagnosis of HDFN is confirmed in patients with suspected HDFN by demonstrating antibody-mediated hemolysis by either a positive direct or indirect antiglobulin test (DAT/IAT; Coombs test). The cost of screening needs to be balanced with the benefit of identifying infants with incompatible blood types to their mothers, as they are at risk for both severe hyperbilirubinemia and hemolytic anemia [3]. In our practice, we suggest that all infants born to a type O mother be tested to identify their blood type and a DAT performed, as they are at risk for HDFN. ABO incompatibility remains a significant cause of extreme neonatal hyperbilirubinemia throughout the world [11]. Other evidence indicates that if a universal bilirubin screening and management program is in place, screening of all neonates born to type O women may not be necessary and may result in cost saving [6]. (See 'ABO hemolytic disease' above.)

A negative DAT does not exclude the diagnosis of HDFN, particularly in the setting of ABO incompatibility or intrauterine transfusions to manage RhD alloantibodies during pregnancy.

●A positive DAT demonstrates the presence of maternal antibody on the neonate's RBCs. In this test, agglutination of 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.

●DAT may not detect sensitized RBCs in ABO HDFN, because the A and B antigens are less well developed in neonates than in older children and adults. In addition, the antigenic sites are fewer and farther apart on neonatal RBCs, making agglutination with the Coombs reagent more difficult [5].

●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 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 anti-human globulin (Coombs serum). Agglutination of red cells coated with maternal antibody indicates the presence of free maternal antibodies in the neonatal serum and a positive IAT [12].

●In infants with Rh HDFN who have received intrauterine transfusions, the DAT may be negative because the presence of donor Rh-negative RBCs makes agglutination more difficult. In contrast, the IAT will remain strongly positive.

Cord blood is often used to identify the infant's blood type and perform DAT. However, a false positive DAT may occur due to contamination of the cord blood sample with Wharton's jelly [13]. In addition, it is not clear whether cord blood testing is less reliable than testing samples obtained directly from the infant [14,15]. It appears that cord blood samples stored for seven or more days are unreliable. In most cases, confirmation of cord blood testing should be done with specimens obtained directly from the infant.

In infants with suspected ABO hemolytic disease with both a negative DAT and IAT of the infant's eluted serum, other causes for hyperbilirubinemia should be sought. Specifically, evaluations for glucose-6-phosphate dehydrogenase (G6PD) deficiency, pyruvate kinase deficiency, and the UGT1A1 gene promoter associated with Gilbert syndrome should be performed. (See "Unconjugated hyperbilirubinemia in the newborn: Pathogenesis and etiology" and 'Differential diagnosis' below.)

For infants with confirmed ABO hemolytic disease but who have persistently elevated bilirubin concentrations, evaluation for other risk factors should be performed [16-18]. For these neonates, two or more factors, each with a minor impact on the total serum bilirubin, can interact in a synergistic manner resulting in extremely high bilirubin concentrations and even kernicterus [19].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis for HDFN includes other causes of neonatal jaundice and hemolytic anemia. HDFN is differentiated from the following disorders by the presence of a positive direct or indirect antiglobulin test (DAT/IAT; Coombs test). These disorders can occur concomitantly in an infant with HDFN. Hyperbilirubinemia may be particularly severe in infants with more than one cause of hyperbilirubinemia [20,21].

The differential diagnosis of unconjugated hyperbilirubinemia and/or anemia during the neonatal period includes the following disorders. Additional characteristics and diagnostic steps are discussed in separate topic reviews (see 'Diagnosis' above and "Unconjugated hyperbilirubinemia in the newborn: Pathogenesis and etiology"):

●Erythrocyte membrane defects – The peripheral blood smear and the negative antiglobulin tests distinguish the inherited erythrocyte membrane defects, such as hereditary spherocytosis [22] (picture 1) or elliptocytosis (picture 2), from HDFN [23]. (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 HDFN. (See "Unconjugated hyperbilirubinemia in the newborn: Pathogenesis and etiology", section on 'Gilbert syndrome'.)

ANTENATAL MANAGEMENT — In developed countries, routine antenatal care includes screening for maternal antibodies that can potentially cause HDFN. If such antibodies are detected, management is directed toward monitoring maternal antibody titers and the condition of the fetus (ie, fetal anemia) and, if necessary, intervening with fetal red blood cell (RBC) transfusions. Antenatal care and the prevention of maternal Rhesus (Rh) sensitization have significantly reduced the number of infants born with severe manifestations of HDFN and is discussed 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 cells".)

POSTNATAL MANAGEMENT — Postnatal management for affected infants is focused on treating the anemia and hyperbilirubinemia caused by hemolysis of neonatal red blood cells (RBCs). The duration of the anemia in infants with HDFN depends on the severity of the anemia at presentation, the timing of onset (early versus late type), and the treatments that are selected.

Delivery room management — 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.

In all cases, if HDFN is suspected or known, cord blood should be sent for the following [24]:

●Blood type and antiglobulin (Coombs) test to confirm the diagnosis

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

●Cross match for subsequent transfusion (see "Red blood cell transfusions in the newborn", section on 'Hemolytic disease of the newborn')

Early anemia — The management of early-onset anemia caused by alloimmune hemolysis is based on the severity of anemia.

Life-threatening severe 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), emergent transfusion with group O, Rhesus D (Rh[D])-negative RBCs is required to stabilize the cardiovascular system [25]. Because of the concern for fluid overload resulting in further compromising myocardial function, the initial volume administered is 10 mL/kg. Thoracentesis or paracentesis may be required in infants with significant respiratory distress due to pleural effusions and/or ascites [26]. (See "Neonatal resuscitation in the delivery room", section on 'Volume expansion' and "Postnatal care of hydrops fetalis", section on 'Initial resuscitation'.)

●After cardiovascular stabilization, early exchange transfusion in the neonatal intensive care unit (NICU) is typically performed to reduce hemolysis and correct anemia, thereby improving oxygenation [26]. (See 'Symptomatic anemia and stable cardiovascular status' below.)

Infants with RhD and some minor blood group incompatibilities, such as Kell, are at risk for hydrops fetalis. The status of a newborn with HDFN 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 emergently transfuse packed group O, RhD-negative RBCs in neonates with severe life-threatening anemia. (See 'Hydrops fetalis' above and "Postnatal care of hydrops fetalis", section on 'Management'.)

Symptomatic anemia and stable cardiovascular status — Transfusion with cross-matched RBCs is indicated in infants with symptomatic anemia (eg, lethargy or tachycardia) and who do not have signs of circulatory collapse. In our institution, the choice between exchange and simple transfusion is based on the severity of hyperbilirubinemia defined by the American Academy of Pediatrics (AAP) guidelines using hour-specific bilirubin values (calculator 1) and anemia as follows:

●For patients with severe anemia (hematocrit <25 percent) and severe hyperbilirubinemia, 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.

Our criteria for exchange transfusion for hyperbilirubinemia are based on the AAP guidelines for the management of hyperbilirubinemia (figure 1) (calculator 1) [27]. The AAP guidelines 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 infants: Management", section on 'Exchange transfusion' and "Unconjugated hyperbilirubinemia in the newborn: Interventions", section on 'Exchange transfusion'.) There is insufficient evidence to support or to refute the use of single volume exchange transfusion versus a double volume exchange transfusion for neonates who meet criteria for exchange transfusion [28].

Early exchange transfusions require skilled and available personnel to perform the procedure. If there is a delay or inability to perform an exchange transfusion, simple transfusion with packed RBCs may be used, recognizing that repeat transfusions may be necessary because of ongoing hemolysis. In addition, the use of intravenous immune globulin (IVIG) has reduced the need for exchange transfusion especially in infants with ABO hemolytic disease.

●For patients with moderate to severe anemia (hematocrit between 25 and 35 percent) and nonsevere hyperbilirubinemia, a simple transfusion is performed.

●For patients with mild or no anemia (hematocrit >35 percent) and nonsevere hyperbilirubinemia who are at risk for late anemia, we treat with darbepoetin or recombinant human erythropoietin (rhEPO; epoetin alfa) and iron supplementation to avoid subsequent transfusion [29]. However, the indications for and benefits of darbepoetin or rhEPO in these patients have not been established. In our center, we prefer to use darbepoetin rather than rhEPO for this purpose. (See 'Late anemia' below.)

The selection of appropriate blood products for RBC transfusions in infants with HDFN is outlined in the table (table 2) and discussed separately. (See "Red blood cell transfusions in the newborn", section on 'Hemolytic disease of the newborn'.)

Asymptomatic anemia — If the patient is asymptomatic, interventions to correct the infant's anemia are not required, but exchange transfusion may still be needed because of severe hyperbilirubinemia. (See "Unconjugated hyperbilirubinemia in term and late preterm infants: Management", section on 'Exchange transfusion' and 'Hyperbilirubinemia' below and "Unconjugated hyperbilirubinemia in the newborn: Interventions", section on 'Exchange transfusion'.)

Late anemia — Late-onset anemia presenting one to three weeks after birth may be seen in neonates with ABO [30], minor blood groups (eg, Gerbich [31] and Kell system [32]), and Rh [33] incompatibilities. Late-onset anemia may be due to immune destruction of erythroid progenitors [31]. In infants who received intrauterine transfusions, hemolytic anemia may also be delayed until the majority of the donor RBCs is replaced with the RBCs of the affected infant (which express the alloimmune antigen and, therefore, are vulnerable to persistent maternal antibody-mediated hemolysis). Finally, anemia may be accentuated by the suppression of erythropoiesis, which normally occurs for all neonates at three to four weeks of age.

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 blood loss [29].

●Infants with symptomatic late-onset anemia are generally treated with simple transfusion.

●rhEPO, or its longer-acting analog darbepoetin, is sometimes used in selected infants in an effort to reduce or prevent the need for transfusion. This includes infants with Kell, Rh, or ABO incompatibility with progressive anemia but who are not yet sufficiently symptomatic to require transfusion, or families whose religious tradition prohibits transfusion. The rhEPO is given subcutaneously at a dose of 400 international units/kg given three times weekly for two weeks [29]. If darbepoetin is used, it is given as a single 4 microg/kg subcutaneous dose every one to two weeks. These infants are also treated with supplemental iron (6 mg/kg per day for those infants on enteral feedings). Longer courses of rhEPO or darbepoetin also may be beneficial [32,33]. Of note, rhEPO or darbepoetin treatment does not usually produce an elevation in hematocrit for at least five days [29].

In our center, we prefer to use darbepoetin rather than rhEPO for this purpose. This is because darbepoetin treatment requires fewer subcutaneous injections for the infant (usually a single dose for darbepoetin for this group of patients, versus three to five injections over two weeks for rhEPO), with similar cost and effect on RBC production. To minimize the cost of darbepoetin treatment, all eligible patients can be treated on the same day, allowing the pharmacy to use a single vial of darbepoetin to obtain the dose for all of the patients. The cost of darbepoetin would be higher in centers that are not able to divide the vial among multiple eligible patients.

Erythropoiesis stimulating agents (ESAs) including recombinant epoetin alfa or darbepoetin require time to have an effect, and the response to therapy needs to be taken into consideration with this time course. (See "Anemia of prematurity", section on 'Erythropoiesis stimulating agents'.)

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 a known hemolytic anemia who have hemoglobin/hematocrits below the normal range prior to the period of time when physiologic anemia is known to occur should be considered at risk for an exaggerated physiologic anemia and be monitored closely.

Hyperbilirubinemia — The treatment of unconjugated neonatal hyperbilirubinemia is discussed in greater detail separately. The following is a summary of the management of hyperbilirubinemia in infants with HDFN. (See "Unconjugated hyperbilirubinemia in term and late preterm infants: Management".)

In infants with hyperbilirubinemia due to HDFN, monitoring serum bilirubin levels, oral hydration, and phototherapy are the mainstays of management. For infants who do not respond to these conventional measures, intravenous (IV) fluid supplementation and/or exchange transfusion may be necessary to treat hyperbilirubinemia. Exchange transfusion may also be required for infants who demonstrate signs of acute bilirubin encephalopathy (ABE). IVIG also may be useful in reducing the need for exchange transfusion.

Ongoing monitoring — The duration of clinical symptoms is variable in infants with HDFN and depends on the following factors. As a result, infants with HDFN require continued ongoing monitoring until their bilirubin concentrations are in a safe range and trending down, without ongoing treatment.

●Since there is considerable variation in the strength of the reactivity of the various antigens involved in HDFN, 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 [34].

●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.

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 guidelines for the initiation and discontinuation of phototherapy based upon total serum bilirubin (TSB) values at specific hourly age of the patient, gestational age, and the presence or absence of risk factors for hyperbilirubinemia, including HDFN (figure 2). (See "Unconjugated hyperbilirubinemia in term and late preterm infants: Management", section on 'Phototherapy' and "Unconjugated hyperbilirubinemia in the newborn: Interventions", section on 'Phototherapy'.)

Hydration — Phototherapy increases insensible skin losses, and as a result the fluid requirements of infants undergoing phototherapy are increased. In addition, byproducts of phototherapy are eliminated in the urine. If oral hydration is inadequate, IV hydration may be necessary. (See "Unconjugated hyperbilirubinemia in the newborn: Interventions", section on 'Hydration'.)

Exchange transfusion — Exchange transfusion is used to treat severe anemia, as previously discussed, and severe hyperbilirubinemia. Exchange transfusion removes serum bilirubin and decreases hemolysis by the removal of antibody-coated neonatal RBCs and unbound maternal antibody. (See 'Symptomatic anemia and stable cardiovascular status' above.)

Immediate exchange transfusion is recommended if the infant demonstrates signs of ABE, such as lethargy, hypotonia, poor sucking, or high-pitched cry. (See "Unconjugated hyperbilirubinemia in term and late preterm infants: Management", section on 'Exchange transfusion' and "Unconjugated hyperbilirubinemia in term and late preterm infants: Epidemiology and clinical manifestations", section on 'Acute bilirubin encephalopathy' and "Unconjugated hyperbilirubinemia in the newborn: Interventions", section on 'Exchange transfusion'.)

The optimal threshold for initiating exchange transfusion in infants with HDFN to prevent ABE is unknown [26]. Based upon clinical practice, a cord bilirubin level greater than 4.5 mg/dL (77 mmol/L) has been suggested as an initial threshold for exchange transfusion [35]. However, others have suggested that cord bilirubin levels are not useful in predicting postnatal TSB levels in neonates with HDFN [36]. An alternative method uses a rise of TSB greater than 0.5 mg/dL (8 mmol/L) per hour, despite intensive phototherapy, as an indication for exchange transfusion [26,36].

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). With prenatal diagnosis and management of HDFN and the use of IVIG, few infants require exchange transfusions. Selection of blood products for transfusion is outlined in the table (table 2) and discussed in a separate topic review. (See "Red blood cell transfusions in the newborn", section on 'Hemolytic disease of the newborn'.)

Immune globulin therapy — Although data are inconclusive [37], our practice is to administer IVIG to infants with severe HDFN in an effort to avoid exchange transfusions. In our practice, we follow the AAP guidelines, which recommend the administration of IVIG in infants with HDFN if the TSB is rising despite intensive phototherapy or is within 2 or 3 mg/dL (34 to 51 micromol/L) of the threshold for exchange transfusion [27]. The recommended dose is 500 to 1000 mg/kg given over two hours, and the dose may be repeated in 12 hours if necessary. (See "Unconjugated hyperbilirubinemia in term and late preterm infants: Management", section on 'Intravenous immune globulin (IVIG)'.)

The proposed mechanism for IVIG is inhibition of hemolysis by blocking antibody receptors on RBCs. Limited data exist for its use in other blood group incompatibilities, such as anti-C and anti-E disease [38,39]. Although several clinical trials have demonstrated that IVIG reduces the need for exchange transfusion for hyperbilirubinemia in infants with hemolytic disease caused by Rh or ABO incompatibility [38,40-45], a systematic review of the literature reported that data regarding the efficacy of IVIG were inconclusive [46]. This conclusion was based on the evaluation of the quality of evidence that showed studies demonstrating efficacy were at high risk for bias, whereas those with low risk of bias did not show benefit from IVIG therapy. There are also limited observational data that IVIG may decrease the risk of neurological impairment, which was not an outcome addressed by the systematic review [47,48]. Further investigation, which may require a large multicenter trial, is needed to determine the efficacy and safety of IVIG therapy in neonates with alloimmune hemolytic disease [49].

Administration of IVIG has been associated with fever, allergic reactions, fluid overload, and rebound hemolysis [50].

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 infants: Management", section on 'Unproven pharmacologic agents'.)

Breastfeeding — Although maternal antibodies are present in breast milk, very little antibody is absorbed [51]. Thus, mothers should be encouraged to breastfeed without restrictions. (See "Initiation of breastfeeding".)

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

●Hemolytic disease of the newborn (HDFN) is caused by the destruction of red cells of the neonate or fetus by maternal immunoglobulin G (IgG) antibodies. Incompatibility between mother and offspring of a major blood group (Rhesus [Rh] and ABO) or minor blood group (Kell, Duffy, MNS, and P systems) causes HDFN that may result in clinically significant neonatal anemia and/or hyperbilirubinemia. If the hyperbilirubinemia is severe in ABO incompatibility, other causes for the hemolytic disease should be sought.

Clinical presentation and diagnosis

●Alloimmune HDFN primarily involves the major blood groups of Rh, A, B, AB, and O. However, minor blood group incompatibilities (Kell, Duffy, MNS, and P systems) can also result in significant disease (table 1).

•Rh incompatibility is the most common cause of HDFN. Clinical manifestations of Rh HDFN range from mild, self-limited hemolytic disease to hydrops fetalis. (See 'RhD hemolytic disease' above and "RhD alloimmunization in pregnancy: Overview".)

•Infants with ABO HDFN generally have less severe disease than those with Rh hemolytic disease. Affected infants are usually asymptomatic at birth and develop hyperbilirubinemia within the first 24 hours of birth. Anemia is usually either absent or mild. For those that develop severe hemolytic disease with resultant extreme hyperbilirubinemia, other causes for the hemolysis should be evaluated. (See 'ABO hemolytic disease' above.)

•The clinical disease associated with HDFN due to other blood groups ranges from mild (hyperbilirubinemia) to severe manifestations, including hydrops fetalis. In particular, anti-Kell HDFN can be severe and may require intrauterine intervention. (See 'Other blood group antibodies' above and "Management of non-RhD red blood cell alloantibodies during pregnancy".)

●HDFN is clinically suspected if there is documented hemolysis based on a peripheral blood smear in a neonate and incompatibility of blood types between the mother and her infant. The diagnosis is confirmed by the demonstration of antibody-mediated hemolysis either by a positive direct or indirect antiglobulin tests (DAT/IAT; Coombs test). (See 'Diagnosis' above.)

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

●The degree of anemia varies in infants with HDFN. Anemia may present at birth (early) or not until one to three weeks of age (late). (See 'Antenatal management' above.)

●In infants with HDFN, hyperbilirubinemia generally presents within the first 24 hours of life. (See 'Clinical presentation' above.)

Management — The postnatal management for HDFN is dependent on both the severity of anemia and hyperbilirubinemia:

●For infants with HDFN with shock or pending shock due to severe anemia (hydrops fetalis), we recommend emergent transfusion using group O, RhD-negative red blood cells (RBCs) versus cross-matched RBCs (Grade 1C). (See 'Life-threatening severe anemia (hydrops fetalis)' above.)

●For infants who have early moderate to severe symptomatic anemia without signs of circulatory compromise, we recommend a transfusion with cross-matched RBCs (Grade 1C). Selection of RBCs for transfusion depends on the type of HDFN (table 2).

In these patients, the choice between exchange and simple transfusion is based upon the following considerations (see 'Early anemia' above and 'Hyperbilirubinemia' above):

•If an infant has findings suggestive of acute bilirubin encephalopathy (ABE) and hyperbilirubinemia, we recommend an exchange transfusion be performed (Grade 1B).

•If an infant has severe anemia and hyperbilirubinemia without signs of ABE, we suggest performing an exchange transfusion for hematocrit <25 percent or based upon the bilirubin threshold levels as outlined by the American Academy of Pediatrics (AAP) (figure 1) (calculator 1) (Grade 2C).

•If the hyperbilirubinemia is not severe and the symptoms of anemia are moderate, we suggest performing a simple transfusion (Grade 2C).

•A simple transfusion may be performed if there is a delay in performing an exchange transfusion. (See "Unconjugated hyperbilirubinemia in term and late preterm infants: Management", section on 'Exchange transfusion' and "Unconjugated hyperbilirubinemia in the newborn: Interventions", section on 'Exchange transfusion'.)

●If hyperbilirubinemia is not severe and the symptoms of early anemia are mild, but the infant is at risk for late anemia, we suggest administering darbepoetin and iron (Grade 2C). Recombinant erythropoietin (rhEPO) is a reasonable alternative but requires more frequent dosing. (See 'Late anemia' above.)

●For infants with late-onset symptomatic anemia, we suggest simple transfusion of cross-matched blood rather than no intervention (Grade 2C). (See "Red blood cell transfusions in the newborn", section on 'Hemolytic disease of the newborn'.)

●Management of hyperbilirubinemia due to HDFN includes monitoring serum bilirubin levels, oral hydration, and phototherapy, which is based on the criteria outlined by the AAP (figure 2). For infants who do not respond to conventional measures, intravenous (IV) fluid supplementation, intravenous immune globulin (IVIG), and exchange transfusion may be used. (See "Unconjugated hyperbilirubinemia in term and late preterm infants: Management" and 'Hyperbilirubinemia' above and 'Breastfeeding' above.)