Continuing Education Activity

Hemolytic disease of the fetus and newborn (HDFN), also known as erythroblastosis fetalis or alloimmune HDFN, occurs when maternal immunoglobulin G (IgG) antibodies target and destroy fetal red blood cells that express antigens not present in the mother. This immune response, termed isoimmunization, leads to fetal hemolysis, subsequent release of bilirubin, and potentially severe anemia. Diagnostic evaluation typically involves monitoring maternal antibody titers via serial amniocentesis between 16 and 20 weeks of gestation to detect signs of fetal anemia, necessitating further invasive testing and potential interventions. Management of HDFN involves close monitoring of maternal antibody titers through serial amniocentesis and fetal ultrasound assessments to detect signs of fetal anemia or hydrops. Treatment may include intrauterine transfusions to manage severe fetal anemia or early delivery if fetal distress is detected.

This activity educates healthcare professionals on the pathophysiology, assessment, and management of erythroblastosis fetalis, emphasizing the critical role of an interprofessional team in administering preventative measures such as RhoGAM (anti-D immunoglobulin or rhesus factor IgG). Collaboration among obstetricians, nurses, and laboratory specialists ensures timely administration of RhoGAM to patients who are Rhesus-negative following sensitizing events like miscarriage or invasive procedures, reducing the risk of maternal sensitization. 

Objectives:

• Identify maternal-fetal Rhesus blood type incompatibility during initial prenatal assessments to predict the risk of hemolytic disease of the fetus and newborn.
• Differentiate between various causes of fetal hemolysis, such as Rhesus isoimmunization versus other non-immune causes, through comprehensive clinical evaluation and diagnostic tests.
• Implement evidence-based protocols for administering RhoGAM (anti-D immunoglobulin) promptly after sensitizing events to prevent maternal sensitization and reduce the risk of hemolytic disease of the fetus and newborn.
• Implement care coordination among interprofessional team members to optimize outcomes for patients with erythroblastosis fetalis.

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. The formation of maternal antibodies in response to a fetal antigen is called isoimmunization. These antibodies form when fetal erythrocytes with specific RBC antigens not expressed in the mother cross the placenta and gain access to maternal blood. This antibody response may be sufficient to destroy fetal red cells, leading to hemolysis, the release of bilirubin, and anemia. The severity of the illness in the fetus depends on various factors, including the amount and strength of antibodies produced by the mother, the fetus's gestational age, and the fetus's ability to replenish the destroyed RBCs and clear bilirubin.

Etiology

Numerous blood group systems are involved in HDFN, including ABO, Rhesus (Rh), Kell, Duffy, Kidd, MNS, Diego, Lutheran, and Xg. Rhesus and ABO are by far the most common. ABO incompatibility generally occurs in a group O mother with a group A or B baby, but ABO incompatibility causes less severe hemolytic disease of the newborn than does Rh(D) incompatibility. Infants are usually asymptomatic at birth with absent or mild anemia and develop neonatal jaundice, successfully treated with phototherapy. A definitive management plan is required because Rhesus factor incompatibility is a severe condition.[1][2]

Epidemiology

The introduction of postnatal immunoprophylaxis in 1970 reduced the incidence of maternal RhD alloimmunization from 14% to 1% or 2%. Subsequently, antenatal immunoprophylaxis was also started, reducing RhD alloimmunization to 0.1%. In the Western world, ABO incompatibility is now the single largest cause of HDFN. The incidence of Rh incompatibility varies by race and ethnicity. Approximately 15% of White individuals are Rh-negative, compared with only 5% to 8% of Black individuals and 1% to 2% of Asians and Native Americans. Among White individuals, an Rh-negative woman has an approximate 85% chance of mating with an Rh-positive man, 60% of whom are heterozygous and 40% of whom are homozygous at the D locus.[3][4]

Pathophysiology

Following maternal exposure to RhD-positive blood, B-lymphocyte clones that recognize the RBC antigen are established. The primary maternal immune response is the production of dose-dependent IgM isotype. The response occurs in about 15% of pregnancies with 1 mL of Rh-positive cells and 70% after 250 mL of Rh-positive cell exposure. Maternal IgG response occurs later in subsequent pregnancies. The secondary immune response follows repeat exposure to as little as 0.03 mL of Rh-positive cells. Maternal anti-D (IgG) antibodies cross the placenta and attach to Rh antigens on fetal RBCs. RBC destruction occurs by lysis of antibody-coated RBCs by macrophage lysosomal enzymes. The fetus initially responds to the subsequent anemia and tissue hypoxia through reticulocytosis, and a rise in umbilical artery lactate indicates severe fetal anemia. Erythroblastosis fetalis results when RBC destruction exceeds production.[5]

History and Physical

History and physical exam vary based on mild to moderate to severe disease:

• Mild to moderate disease: Less severely affected infants typically present with self-limited hemolytic disease, which presents with hyperbilirubinemia within the first 24 hours of life.
• 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 minor blood group incompatibilities, such as Kell, are at risk for hydrops fetalis, especially in pregnancies without antenatal care.

Evaluation

For patients who are Rh-negative and also have a negative antibody screen, prevention of sensitization during the pregnancy course is imperative. Possible reasons a patient may be exposed to fetal blood and sensitization include miscarriage, amniocentesis, vaginal bleeding, placental abruption, and abdominal trauma. RhoGAM (anti-D immunoglobulin or Rhesus factor IgG) should be administered if these instances occur. The titer is also checked if the antibody screen for Rh is positive during the initial prenatal visit. Antibody titers of 1:16 and greater have been associated with fetal hydrops. If paternity is unclear, blood type can be performed on the father of the baby to determine if the fetus is at risk. Approximately 5% of all pregnancies have unknown or incorrect paternity; therefore, the safest course is to treat all pregnancies as if the fetus is at risk.

Throughout pregnancy, the antibody titer is followed approximately every 4 weeks. The pregnancy can be managed expectantly if the titer remains less than 1:16. However if the titer exceeds 1:16, serial amniocentesis should be started as early as 16 to 20 weeks. At the first amniocentesis, fetal cells can be collected and analyzed for the Rh antigen to determine fetal Rh status. If negative, the pregnancy can be followed expectantly. However, if the fetus is Rh-positive, fetal anemia is screened using fetal middle cerebral artery (MCA) Doppler measurements. More than a decade ago, this was demonstrated in anemic fetuses with greater blood flow to the brain; thus, the MCA Doppler measures peak systolic velocity. In fetuses with greater peak systolic velocity measurements, concern for fetal anemia merits more invasive testing and potential treatment. Historically, before using Doppler ultrasound, the evaluation of an Rh-positive fetus in an Rh-negative woman with positive titers 1:16 or greater was performed with serial amniocenteses to assess the amniotic fluid by a spectrophotometer.[6][7][8]

Treatment / Management

Rho(D) immune globulin prepares human IgG-containing antibodies against the RBCs' Rho(D) antigen. Rho(D) immune globulin prevents Rh hemolytic disease in the newborn. Administration of Rho(D) immune globulin to Rho(D) negative mothers at the time of antigen exposure, such as the birth of a Rho(D)-positive child, blocks the primary immune response to the foreign cells. Therefore, maternal antibodies to Rh-positive cells are not produced in subsequent pregnancies, and hemolytic disease of the neonate is averted. 

RhoGAM should be administered at 28 weeks due to the half-life of about 12 weeks; this protects the mother until term or 40 weeks and postpartum if the neonate is Rh-positive. A standard dose of RhoGAM (0.3 mg) will eradicate 15 mL of fetal RBCs. This dose is adequate for a routine pregnancy. In cases of antepartum bleeding, abdominal trauma, amniocentesis, or placental abruption where more blood is transferred from the fetus to the mother than normal, the standard 0.3 mg dose of RhoGAM may be insufficient. A Kleihauer-Betke test that determines the amount of fetal RBCs in the maternal circulation should be performed. Additional dosages must be given if the amount of fetal RBCs exceeds what a single RhoGAM can eliminate.

Cordocentesis and measurement of fetal hemoglobin are used to assess the severity of anemia when dopplers of the middle cerebral artery are elevated. Fetal hemoglobin is 2 standard deviations below the mean value for gestational age, a hemoglobin level of more than 7 g/dL below the normal mean for gestational age or hydrops (actual hemoglobin level of less than 5 g/dL), and a hematocrit of less than 30% for fetal transfusion.

Differential Diagnosis

The causes of elevated unconjugated bilirubin are vast. The most common cause is physiologic jaundice. Physiologic jaundice presents around day 2 or 3 with serum bilirubin of less than 12 mg/dL, mainly unconjugated. The jaundice commonly disappears by the end of the first week and happens in 60% of term and 80% of preterm infants because of the limited ability to conjugate bilirubin. Risk factors include maternal diabetes, polycythemia, cephalohematoma, prematurity, male sex, Asian descent, Down syndrome, delayed bowel movement or upper gastrointestinal obstruction, hypothyroidism, and a sibling with physiologic jaundice.

Jaundice in the first 24 hours after birth is not physiologic and needs further evaluation. Early-onset breastfeeding jaundice is the most common cause of pathologic unconjugated hyperbilirubinemia. Because of caloric deprivation, breastfeeding can potentiate physiologic jaundice in the first week of life, leading to an increase in enterohepatic circulation and, thus, a decrease in bilirubin reabsorption via the gut. Successful breastfeeding every 2 to 3 hours while monitoring stool and urine output to determine if the infant is feeding adequately decreases the risk of hyperbilirubinemia. Breast milk jaundice occurs after the first week of life and is secondary to breast milk’s ability to inhibit 2,3 uridine diphosphate (UDP) glucuronyltransferase, the enzyme responsible for conjugating bilirubin. Genetic causes of unconjugated hyperbilirubinemia include Gilbert syndrome, which presents with jaundice later in life following mild illnesses, fasting, or physical stress. Gilbert syndrome is due to a UDP glucuronosyltransferase defect. Crigler-Najjar is due to an absence or decrease in UDP glucuronosyltransferase.

Other causes due to an increase in bilirubin production, similar to Rh/ABO incompatibility, include enzyme defects (glucose-6-phosphate deficiency and pyruvate kinase deficiency), structural defects (spherocytosis and elliptocytosis), birth trauma (cephalohematoma and excessive bruising), and polycythemia. The workup for indirect hyperbilirubinemia includes complete blood count, reticulocyte count, blood smear, serum haptoglobin, direct and indirect Coombs test, hemoglobin electrophoresis, red cell enzyme assay, and spherocytosis test.[9][10][11]

Prognosis

The prognosis of this disease has significantly improved over the past few years due to tools and noninvasive treatments. Combined results from several studies (including cases managed by fetal transfusion) reported fetal survival of 94% and 74% for nonhydropic and hydropic fetuses, respectively. In a large series of over 300,000 pregnancies, newborns at risk of HDFN due to alloantibodies other than anti-Rh(D) were more likely to have icterus than those not at risk (25% versus 10%) and to be treated with phototherapy (17% versus 5%).[12][13][14]

Complications

Anemia can lead to high-output cardiac failure or myocardial ischemia. As the cardiac system attempts unsuccessfully to keep pace with the oxygen delivery demands, the myocardium is dysfunctional, resulting in effusions, edema, and ascites due to hydrostatic pressure increases. This combination of fluid accumulation in at least 2 extravascular compartments (pleural effusion, ascites, pericardial effusion, or subcutaneous edema) is called hydrops fetalis.

Unconjugated bilirubin is lipid-soluble and crosses the blood-brain barrier (BBB), causing kernicterus. The risk of kernicterus is higher with indirect bilirubin levels greater than 20 or rising levels after phototherapy. Kernicterus can present with lethargy and poor feeding, followed by a toxic appearance with respiratory distress and decreased deep tendon reflexes. Kernicterus may resemble sepsis, asphyxia, hypoglycemia, and intracranial hemorrhage. The risk of kernicterus is increased with acidosis and sepsis, which increases BBB permeability. The risk is also increased with hypoalbuminemia, which leads to a reduced ability to transport unconjugated bilirubin to the liver. Finally, the risk is worse by drugs that displace bilirubin from albumin, including ceftriaxone. To prevent kernicterus, phototherapy is performed on at-risk infants with elevated bilirubin.[14][15]

Deterrence and Patient Education

The prognosis of this disease has significantly improved due to a multidisciplinary approach toward diagnosis and treatment. The interdisciplinary clinical team now has the tools for noninvasive treatment, which, when performed antenatally, prompts early recognition and treatment—improving patient care.

Enhancing Healthcare Team Outcomes

Pregnancy is usually monitored by an interprofessional team that includes an obstetric nurse. These healthcare professionals must ensure that pregnant individuals do not develop erythroblastosis fetalis as the condition is preventable. Throughout pregnancy, the antibody titer is followed approximately every 4 weeks. The pregnancy can be managed expectantly if the titer remains less than 1:16. However, if the titer exceeds 1:16, serial amniocentesis should be started as early as 16 to 20 weeks.

At the first amniocentesis, fetal cells can be collected and analyzed for the Rh antigen to determine fetal Rh status. If negative, the pregnancy can be followed expectantly. However, if the fetus is Rh-positive, fetal anemia is screened using fetal Doppler measurements. More than a decade ago, greater blood flow to the brain was demonstrated in fetuses with anemia, necessitating middle cerebral artery Doppler, which measures peak systolic velocity. In fetuses with greater peak systolic velocity measurements, concern for fetal anemia merits invasive testing and potential treatment.[7]

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Disclosure: George Nassar declares no relevant financial relationships with ineligible companies.

Disclosure: Elsa Vadakekut declares no relevant financial relationships with ineligible companies.

Disclosure: Cristin Wehbe declares no relevant financial relationships with ineligible companies.