Erythroblastosis Fetalis


Article Author:
George Nassar


Article Editor:
Cristin Wehbe


Editors In Chief:
David Wood
Andrew Wilt
Hajira Basit


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Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
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Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
6/4/2019 7:14:10 PM

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 that express certain RBC antigens that are not expressed in the mother cross the placenta and gain access to maternal blood. This antibody response may be sufficient enough 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 antibody produced by the mother, the gestational age of the fetus, and the ability of the fetus to replenish the destroyed RBCs and clear bilirubin.

Etiology

Numerous blood group systems have been implicated in HDFN including, ABO, Rhesus (Rh), Kell, Duffy, Kidd, MNS, Diego.P, Lutheran, and Xg. [1] 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.[2] Affected infants are usually asymptomatic at birth with absent or mild anemia and develop neonatal jaundice, which is usually successfully treated with phototherapy. Because Rhesus factor incompatibility is more severe, it will be the focus of the rest of this discussion.

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 which further reduced RhD alloimmunization to 0.1%.[3] 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 whites are Rh negative, compared with only 5% to 8% of African Americans and 1% to 2% of Asians and Native Americans. Among whites, 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.[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 IgM isotype. It is important to note that this primary maternal immune response is dose-dependent. It 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.[5] 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.

History and Physical

Mild to Moderate Disease: Less severely affected infants typically present with the self-limited hemolytic disease which is manifested as hyperbilirubinemia within the first 24 hours of life.

Hydrops Fetalis: Infants with severe, life-threatening anemia (e.g., 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.

Evaluation

For patients who are Rh-negative and also have a negative antibody screen, it is important to try and prevent them from becoming sensitized during the pregnancy course. Possible reasons a patient may become exposed to fetal blood and thus sensitized include miscarriage, amniocentesis, vaginal bleeding, placental abruption, and abdominal trauma. If any of these instances occur, RhoGAM (anti-D immunoglobulin or Rhesus factor IgG) should be administered.

If the antibody screen for Rh comes back positive during the initial prenatal visit, the titer is checked as well. Antibody titers of 1:16 and greater have been associated with fetal hydrops. If paternity is not in question, blood type can be performed on the father of the baby to determine whether the fetus is at risk. However, because approximately 5% of all pregnancies have unknown or incorrect paternity, the safest course is to treat all pregnancies as if the fetus is at risk. [6]

Throughout pregnancy, the antibody titer is followed approximately every 4 weeks. As long as it remains less than 1:16, the pregnancy can be managed expectantly. However, if it 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 for, using fetal middle cerebral artery (MCA) Doppler measurements.[7] It was demonstrated more than a decade ago that in anemic fetuses there is greater blood flow to the brain, thus the MCA Doppler measures peak systolic velocity (PSV). In fetuses with greater PSV measurements, concern for fetal anemia merits more invasive testing and potential treatment.[8]

Historically, prior to the use of MCA Doppler, the evaluation of Rh-positive fetus in an Rh-negative woman with positive titers 1:16 or greater was done with serial amniocenteses to assess the amniotic fluid by a spectrophotometer.

Treatment / Management

Rho(D) immune globulin is a preparation of human IgG containing antibodies against the Rho(D) antigen of the red cell. Rho(D) immune globulin is used for prevention of Rh hemolytic disease of 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 since it has a half-life of about 12 weeks and covers 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 not be sufficient. A Kleihauer-Betke test that determines the amount of fetal RBCs in the maternal circulation should be performed. If the amount of fetal RBCs is more than can be eliminated by the single RhoGAM dose, additional dosages must be given.

Cordocentesis and measurement of fetal hemoglobin are used to assess the severity of anemia when MCA dopplers are elevated. Fetal hemoglobin is two 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). A hematocrit of less than 30% also can be used as the threshold for fetal transfusion.

Differential Diagnosis

Causes of elevated unconjugated bilirubin are vast. The most common cause is physiologic jaundice. Physiologic jaundice presents around day 2 or 3 with a serum bilirubin of less than 12 mg/dL, mainly unconjugated. It commonly disappears by the end of the first week and happens in 60% of term and 80% of preterm infants because of limited ability to conjugate bilirubin.[9] Risk factors include maternal diabetes, polycythemia, cephalohematoma, prematurity, male, Asian, Down syndrome, delayed bowel movement or upper gastrointestinal obstruction, hypothyroid, and a sibling with physiologic jaundice.

Jaundice in the first 24 hours after birth is not physiologic jaundice and needs further evaluation. Early-onset breastfeeding jaundice is the most common cause of pathologic unconjugated hyperbilirubinemia. Breastfeeding can potentiate physiologic jaundice in the first week of life because of caloric deprivation, 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, significantly decreases the risk of hyperbilirubinemia. [10]

Breast milk jaundice occurs after the first week of life and is secondary to breast milk’s ability to inhibit 2,3 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 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 work-up for indirect hyperbilirubinemia includes CBC, reticulocyte count, blood smear, serum haptoglobin, direct and indirect Coombs test, hemoglobin electrophoresis, red cell enzyme assay, and spherocytosis test.[11]

Prognosis

The prognosis of this disease has significantly improved over the past few years thanks to the developments of tools and noninvasive testament, which when performed antenatally will prompt early recognition and treatment.

  • Combined data from several studies that included cases managed by fetal transfusion reported fetal survival of 94% and 74% for nonhydropic and hydropic fetuses respectively.[12]
  • In a large series of over 300,000 pregnancies, those 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%).[13][14]

Complications

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

Unconjugated bilirubin is lipid soluble, thus giving it the ability to cross the blood-brain barrier (BBB) and cause kernicterus. The risk of kernicterus is higher with indirect bilirubin levels greater than 20 or rising levels despite phototherapy.[14] 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 made worse by drugs that displace bilirubin from albumin, including ceftriaxone. To prevent kernicterus, phototherapy is done on at-risk infants with elevated bilirubin.[15]

Deterrence and Patient Education

The prognosis of this disease has significantly improved due to a multidisciplinary approach toward diagnosis and treatment. The team of nurses and physicians now have the tools and noninvasive testament, which when performed antenatally will prompt early recognition and treatment and improve the care of the patient. [Level V]

Enhancing Healthcare Team Outcomes

Pregnancy is usually followed by a multidisciplinary team that includes the obstetric nurse. These professionals need to ensure that pregnant women do not develop erythroblastosis fetalis, because it is preventable. Throughout pregnancy, the antibody titer is followed approximately every 4 weeks. As long as it remains less than 1:16, the pregnancy can be managed expectantly. However, if it 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 for, using fetal middle cerebral artery (MCA) Doppler measurements.[7] It was demonstrated more than a decade ago that in anemic fetuses there is greater blood flow to the brain, thus the MCA Doppler measures peak systolic velocity (PSV). In fetuses with greater PSV measurements, concern for fetal anemia merits more invasive testing and potential treatment.


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Erythroblastosis Fetalis - Questions

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Which of the following does NOT characterize erythroblastosis fetalis?



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A 30-year-old G2P1 female presents to labor and delivery at term with regular contractions and a gush of fluid. The mother is noted to be Rh-negative, and her husband is Rh-positive. Due to complications, manual removal is required to deliver the fetus. To determine the appropriate amount of Rho(D) immune globulin that should be administered, which laboratory test is most appropriate?



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A 1-day-old neonate presents with skin edema, pericardial effusion, and ascites. Which of the following is the most likely explanation?



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A 1-day-old neonate presents with jaundice, anemia, head retractions, and edema in the extremities and trunk. Labs are pending. Which of the following is the most likely cause?



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A 27-year-old G2P1 woman is diagnosed with Rh hemolytic disease at 25 weeks gestation. To determine the severity of her disease, which of the following should be measured in the amniotic fluid?



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A neonate is recently born and determined to have hemolytic disease of the newborn. Both parents are Rh-positive. IgG antibodies are found in the mother's blood. Which combination of blood types is most likely the result of the neonates condition?



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A 32-year-old G6T3P0A2L2 presents to the clinic with concerns about her pregnancy. She is Rh-negative, and her husband is Rh-positive. She has two living children who are also Rh-negative. She had one child who died shortly after birth with erythroblastosis fetalis. To determine if the mother has circulating anti-Rh antibodies, which test should be performed?



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A 23-year-old G2P1 mother with maternal anti-D titers greater than 1:16 comes in for Doppler assessment at 29 weeks. The optical density deviation results at 450 nm plot on the Liley curve in zone 3. Which of the following is the best next step in managing this patient?



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Erythroblastosis Fetalis - References

References

Fetal anemia due to non-Rhesus-D red-cell alloimmunization., Moise KJ,, Seminars in fetal & neonatal medicine, 2008 Aug     [PubMed]
Lessons learned from the implementation of non-invasive fetal RHD screening., Clausen FB,, Expert review of molecular diagnostics, 2018 May     [PubMed]
A brief overview of clinical significance of blood group antibodies., Gandhi MJ,Strong DM,Whitaker BI,Petrisli E,, Immunohematology, 2018 Jan     [PubMed]
Practice Bulletin No. 181 Summary: Prevention of Rh D Alloimmunization.,, Obstetrics and gynecology, 2017 Aug     [PubMed]
Learning from claims: hyperbilirubinaemia and kernicterus., Rennie JM,Beer J,Upton M,, Archives of disease in childhood. Fetal and neonatal edition, 2018 May 25     [PubMed]
Update on Phototherapy in Jaundiced Neonates., Ebbesen F,Hansen TWR,Maisels MJ,, Current pediatric reviews, 2017     [PubMed]
Hyperbilirubinemia in the newborn., Lauer BJ,Spector ND,, Pediatrics in review, 2011 Aug     [PubMed]
Successful management of severe red blood cell alloimmunization in pregnancy with a combination of therapeutic plasma exchange, intravenous immune globulin, and intrauterine transfusion., Nwogu LC,Moise KJ Jr,Klein KL,Tint H,Castillo B,Bai Y,, Transfusion, 2018 Mar     [PubMed]
Hemolytic disease of the fetus and newborn: Current trends and perspectives., Basu S,Kaur R,Kaur G,, Asian journal of transfusion science, 2011 Jan     [PubMed]
Liumbruno GM,D'Alessandro A,Rea F,Piccinini V,Catalano L,Calizzani G,Pupella S,Grazzini G, The role of antenatal immunoprophylaxis in the prevention of maternal-foetal anti-Rh(D) alloimmunisation. Blood transfusion = Trasfusione del sangue. 2010 Jan;     [PubMed]
Hartwell EA, Use of Rh immune globulin: ASCP practice parameter. American Society of Clinical Pathologists. American journal of clinical pathology. 1998 Sep;     [PubMed]
Andrei C,Vladareanu R, The value of reference ranges for middle cerebral artery peak systolic velocity in the management of rhesus alloimmunized pregnancies. Maedica. 2012 Jan;     [PubMed]
Lee L,Nasser J, Doppler ultrasound assessment of fetal anaemia in an alloimmunised pregnancy. Australasian journal of ultrasound in medicine. 2010 Nov;     [PubMed]
Barcellini W,Fattizzo B, Clinical Applications of Hemolytic Markers in the Differential Diagnosis and Management of Hemolytic Anemia. Disease markers. 2015;     [PubMed]
Kirk JM, Neonatal jaundice: a critical review of the role and practice of bilirubin analysis. Annals of clinical biochemistry. 2008 Sep;     [PubMed]

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