Hemolytic Disease of the Fetus and Newborn

Hemolytic disease of the fetus and newborn (HDFN), also known as erythroblastosis fetalis, is caused by maternal IgG antibody destruction of the fetal RBCs. Rhesus (Rh) blood group incompatibility (frequently triggered by D antigen) and ABO incompatibility are common causes. In Rh incompatibility, an RhD-negative mother carries an RhD-positive baby; thus, antibodies form against antigens when fetal RBCs cross into the maternal circulation. In ABO incompatibility, commonly, a mother with blood type O has existing antibodies to A and B antigens. The affected baby can suffer from hemolytic anemia leading to severe neonatal jaundice, hydrops fetalis, cardiac complications, and fetal demise. If the pregnancy is affected by Rh incompatibility, antenatal surveillance is done to determine the need for intrauterine transfusion and early delivery. Postnatal treatment includes close monitoring, phototherapy for jaundice, and exchange transfusion in severe cases. For RhD-negative mothers, maternal sensitization can be prevented by using anti-D immunoglobulin (RhoGAM). Prognosis is excellent with prenatal care, blood type screening, and availability of RhD immune globulin.

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Overview

Definition

Hemolytic disease of the fetus and newborn (HDFN) is hemolytic anemia of the fetus or newborn of varying degrees of severity due to maternal IgG antibodies against fetal RBC surface antigens.

  • Also known as alloimmune HDFN or erythroblastosis fetalis
  • Antigens involved: 
    • ABO
    • Rhesus (Rh) factor (most commonly the D antigen)
    • Minor red cell antigens (Kell, Duffy, Kidd antigens)

Epidemiology

  • Rh incompatibility remains the most common cause of HDFN worldwide.
  • In the United States, 15% of the population is Rh negative.
  • HDFN due to ABO mismatch occurs when the mother is blood type O+ (has anti-A and anti-B antibodies): 
    • Jaundice (hyperbilirubinemia) more frequently seen versus hemolysis
    • Anemia is less severe in ABO incompatibility in most cases compared to sensitized Rh incompatibility. 
  • Recognition of the increased risk factors for maternal exposure to RBC antigens has significantly improved the prevention and management of HDFN.
  • Current Rhogam recommendations, when followed, can reduce RhD alloimmunization to 0.2% in mothers at risk.

Etiology

  • Maternal antibodies must be of the IgG class to cross the placenta.
  • Maternal antibodies (to fetal antigens) that are formed depend on the blood group and result in different types of HDFN:
    • ABO hemolytic disease:
      • Major blood groups: A, B, AB, O
      • A and/or B antibodies are naturally produced against the antigens that are not innately present (e.g., type O has anti-A and anti-B antibodies). 
      • Seen in 15% of pregnancies 
    • RhD hemolytic disease:
      • Rh (positive or negative based on the expression of D antigen in RBCs)
      • RhD negative status is due to the absence or alteration of the RHD gene.
      • HDFN usually occurs during the 2nd exposure when the antibodies involved are IgG.
    • Minor blood groups (33 total blood group systems), such as:
      • Kell (anti-Kel-1 antibody: a rare but severe cause of HDFN, which is life threatening)
      • Duffy
      • Kidd
  • Other risk factors for maternal exposure to incompatible RBC antigens:
    • Known fetal-maternal hemorrhage (FMH):
      • Placental abruption and other placental bleeding or injury
      • Delivery of a previous infant
      • Previous infant with HDFN
      • Fetal surgery
    • Possible FMH events that may have gone unappreciated:
      • Ectopic pregnancy
      • Spontaneous or induced abortion
      • Abnormal placental insertion
      • Fetal demise
      • Amniocentesis and chorionic villus sampling
      • Maternal abdominal trauma
      • Fetal version maneuvers
    • Maternal history with possible transfusion (if it occurred in childhood, the mother may not know the history):
      • Survivor of childhood cancer
      • History of surgery, especially cardiac or other major surgery
      • Prolonged hospital stay as a child
      • Splenectomy without a known cause

Major ABO blood groups with the respective antigens and antibodies based on blood type

Image: “ABO blood type” by InvictaHOG. License: Public Domain

Pathophysiology

During pregnancy, fetal RBCs move across the placenta into the maternal circulation:

  • Usually at low volumes (< 15 mL)
  • Greater risk of FMH and larger volumes (10–150 mL) closer to delivery or under certain circumstances
  • Incompatibility of antigens expressed on the fetal RBCs leads to the formation of maternal antibodies.
  • Type of incompatibility can impact the outcome (ranges from mild to severe anemia and sequela).

ABO incompatibility:

  • Maternal blood group O is at the highest risk: 
    • Fetal blood group A or B
    • Maternal anti-A or anti-B IgG target antigens on the fetal RBCs and cause hemolysis → jaundice (more common) and usually mild anemia
  • Innate, with no sensitization/prior exposure needed 
  • Milder form of HDFN
  • Anti-A antibodies > anti-B antibodies

Rhesus incompatibility:

  • Setting: RhD-negative mother and RhD-positive fetus
  • Prior sensitization needs to occur:
    • 1st pregnancy: Mother develops IgM antibodies (cannot cross the placenta) at the 1st exposure to an Rh-incompatible fetus.
    • The 1st pregnancy will not be affected.
    • Subsequent pregnancies result in maternal anti-D IgG that can cross the placenta and target the RBC RhD antigen of the subsequent fetus.
    • More severe hemolysis causing severe anemia, hydrops, cardiac failure, and severe jaundice 
    • In rare situations, a woman may have been sensitized prior to her 1st pregnancy (e.g., blood transfusion in her childhood).

Rh incompatibility, 1st pregnancy:
Mother is Rh negative and baby is Rh positive in the 1st pregnancy, which triggers the formation of maternal antibodies (IgM). This scenario does not affect the 1st baby.

Image by Lecturio.

Rh incompatibility, 2nd pregnancy:
While the 1st-born baby is not affected, by this time, IgG maternal antibodies have developed, which attack the baby if Rh positive. This scenario can lead to hydrops fetalis, hypoxia, and death.

Image by Lecturio.

Clinical Presentation

Fetus (in utero)

Ultrasound (US) may show evidence of immune hydrops fetalis, a life-threatening condition in which fetuses have abnormal fluid build-up in the body. The US findings of immune hydrops fetalis may include:

  • Polyhydramnios
  • Enlarged placenta
  • Hepatomegaly
  • Splenomegaly
  • Cardiomegaly
  • Generalized edema (including scalp edema, pleural effusion, ascites)

Newborn

Mild-to-moderate disease:

  • No or mild anemia (normal hemoglobin is 19.9 + 2.2 g/dL at birth)
  • Jaundice in the 1st 24 hours of life

Severe disease:

  • Severe anemia (< 10 g/dL)
  • Significant jaundice in the 1st 24 hours of life
  • Kernicterus (a rare condition where high levels of unconjugated bilirubin deposit in parts of the brain leading to encephalopathy) 
  • Hepatosplenomegaly
  • Ascites
  • Edema 
  • Shock

Hydrops fetalis in a newborn, born to a Rhesus negative mother without proper prevention:
Note the generalized edema.

Image: “Le nouveau né en hydrops foetalis” by Service de Gynécologie Obstétrique, Hôpital Militaire d’instruction Mohammed V, Avenue des Far Hay Riad, Rabat, Maroc. License: CC BY 2.0

Diagnosis

General principles

It is important to identify the potential risk factors for unknown sensitization and prior history of HDFN during pregnancy. Potential blood incompatibilities include:

  • ABO incompatibility: 
    • Most anti-A and anti-B antibodies are IgM; therefore, a majority do not cross the placenta.
    • As such, ABO incompatibility is more of a concern postnatally.
  • RhD incompatibility: 
    • Associated with severe risk of HDFN 
    • Only incompatibility that has prophylaxis available; thus, antenatal diagnosis is important
  • Other erythrocyte antibodies capable of causing HDFN:
    • Duffy
    • Kell
    • Kidd
  • Incompatibility with minor blood groups: generally, if a red cell IgG antibody is identified, best to proceed and evaluate for hemolytic disease

Testing the mother

  • Blood type (ABO)
  • Rh status: reflex antibody screening (RhD-negative mothers only)
    • Negative anti-D antibodies: Mother is not sensitized.
    • Positive anti-D antibodies: Mother has been sensitized. 
  • Antibody screening for other erythrocyte antibodies (e.g., anti-Kell) for all mothers:
    • Identify the antibody, if detected.
    • IgM antibodies do not cross the placenta and do not cause HDFN.
    • Get antibody titers of any antibodies known to cause HDFN → higher titers = higher risk for HDFN

Testing the father

  • If maternal antibodies are detected, the father should be tested for the antigen in question.
  • If the father is negative, the infant will not have the antigen:
    • No risk for HDFN 
    • Proceed with routine care.
  • If the father is positive (or unknown), the infant may have the antigen:
    • Infant could be at risk for HDFN
    • Attempt to determine if the father is heterogenous (infant could be at risk) vs. homogenous (infant is at risk).
    • Attempt to determine the fetal genotype.

Testing the fetus

  • Attempt to determine the fetal genotype (and subsequently HDFN risk) via:
    • Maternal serum
    • Amniocentesis
  • Monitor fetus at risk using US (determine the presence of hydrops fetalis) and maternal antibody titers (rise in titers indicates active hemolysis).
  • Monitor for the development of fetal anemia via:
    • US doppler assessment of the fetal middle cerebral artery (MCA)
      • ↑ Peak systolic velocity (PSV) in the MCA indicates “cephalization of flow”
      • “Cephalization of flow” indicates fetal anemia and that the infant is attempting to shunt blood flow to its most critical organ, the brain.
      • ↑ MCA-PSV means ↓ HbF
    • Cordocentesis to obtain a fetal blood sample and measure hemoglobin

Diagnosis of hemolytic disease of the fetus and newborn
A: ultrasound image of the head of the fetus showing scalp edema (arrow); B: ultrasound showing ascites (arrow) on a sagittal section of the abdomen; C: sinusoidal fetal heart-rate pattern seen in patients with severe anemia

Image: “Serious materno-fetal alloimmunization” by Service de Gynécologie Obstétrique, Hôpital Militaire d’instruction Mohammed V, Avenue des Far Hay Riad, Rabat, Maroc. License: CC BY 2.0

Postnatal evaluation

  • Newborn physical exam to determine hemolysis:
    • Respiratory status: tachypnea, distress (can have pleural effusion and pulmonary hypoplasia)
    • Cardiac: murmur
    • Pallor
    • Jaundice (common, but not present at birth in normal/healthy babies)
    • Hepatosplenomegaly, ascites
  • Look for evidence of significant hemolysis:
    • CBC: ↓ hemoglobin after birth 
    • ↑ Indirect bilirubin levels
    • ↑ Reticulocyte count (often)
    • Coomb’s test (+ direct or indirect test)
    • Peripheral smear: ↓ RBCs, macrocytosis, reticulocytosis

Management

Prevention

RhD incompatibilities are the only forms of alloimmunization that can be prevented.

  • RhD-negative women with negative anti-D antibodies: 
    • Recheck antibodies at 28 weeks.
    • Give RhoGAM (anti-D immunoglobulin):
      • At 28 weeks gestation (the time fetal RBCs express D antigens)
      • Within 72 hours of birth
      • After amniocentesis 
      • After chorionic villus sampling
      • If other risks of FMH are suspected (as listed above)
  • Kleihauer-Betke (KB) test considered in cases of potential FMH (i.e., bleeding or miscarriage):
    • Measures fetal hemoglobin (HbF) transferred from a fetus to the mother’s bloodstream
    • Helps decide the additional dosage of RhoGAM, if needed

Prevention of sensitization using anti-D immunoglobulins (RhoGAM):
Anti-D binds Rh negative antigens in the mother’s circulation to avoid sensitization and development of immune response/formation of antibodies versus Rh negative.

Image by Lecturio.

Management of the affected fetus

  • Individuals at risk of HDFN should undergo recommended fetal monitoring.
  • When MCA-PSV reaches the threshold indicative of ↓ hemoglobin, check for anemia:
    • Mild anemia:
      • Serial US monitoring 
      • Delivery at term or when there is adequate lung maturity
    • Severe anemia: 
      • Confirm severe anemia (hemoglobin < 10 g/dL).
      • ≤ 35 weeks gestational age: intrauterine transfusion of packed RBCs (negative for involved antigen and cytomegalovirus, leukodepleted, and irradiated)
      • > 35 weeks gestational age: Consider delivery.
  • Other considerations:
    • If preterm delivery anticipated:
      • Assess maturity of the fetal lung.
      • Consider glucocorticoid steroids for lung maturity.
    • Prepare for delivery where obstetric, maternal-fetal medicine, and pediatric support is available.

Management of the affected newborn

  • Mild HDFN:
  • ABO incompatibility results in jaundice and mild hemolytic anemia.
    • Watch for the following symptoms:
      • Worsening jaundice
      • Poor feeding 
      • Lethargy
      • Irritability
      • Respiratory distress
    • Monitor:
      • Bilirubin levels (and treat accordingly, see management below)
      • Hemoglobin, if clinically indicated
  • Severe HDFN (as seen in RhD incompatibility and Kell alloimmunization):
    • High-risk delivery team available for resuscitation
    • Anemia:
      • Exchange transfusion for severely affected newborns (shock, hydrops fetalis) to reduce hemolysis and improve oxygenation
      • Simple transfusion is an option for newborns without circulatory collapse.
      • Iron supplementation with RBC transfusion (based on severity)
    • Hyperbilirubinemia:
      • Phototherapy
      • Careful fluid management
      • Possible exchange transfusion 
      • For severe cases: IV immunoglobulin (IVIg), which can block RBC antibody receptors, leading to a decrease in hemolysis

Image of neonatal jaundice: newborn undergoing phototherapy

Image: “Jaundice phototherapy” by Martin Pot. License: CC BY 3.0

Prognosis

  • Prognosis is excellent if there is access to prenatal care, ABO blood type screening at birth, and with the use of Rhogam in Rh-negative mothers.
  • Rarer forms of HDFN due to minor blood groups, particularly Kell, can cause severe and often fatal anemia.

Differential Diagnosis

  • Thalassemia: genetic hemoglobinopathies with variable presentations that affect globin chains. More common non-immune hydrops fetalis can be due to genetic causes leading to fluid overload, including other forms of severe anemia such as thalassemia major (rare form with a complete lack of alpha chains). 
  • Hereditary spherocytosis: a relatively common, usually autosomal dominant hemolytic anemia due to a defect in the membrane protein. Newborns with this condition usually present with anemia and neonatal jaundice. Peripheral blood smear shows microspherocytes.
  • Glucose-6-phosphate dehydrogenase deficiency: an intravascular hemolytic anemia, which is inherited in an X-linked recessive manner. Patients have episodic hemolysis due to an identified oxidative stressor that causes damage to RBCs that lack enough NADPH. Newborns with oxidative stress can present with anemia. Peripheral smear shows microspherocytes and “bite cells.”
  • Congenital TORCH infection: TORCH stands for toxoplasmosis, others (syphilis, varicella-zoster virus, parvovirus B19, and human immunodeficiency virus), rubella, cytomegalovirus, and herpes simplex. These infections are associated with fetal loss, stillbirth, intrauterine growth retardation, fetal anemia, jaundice, and hepatosplenomegaly. History, blood tests for infection based on clinical suspicion, and typical examination findings of the different infections aid in pointing to the diagnosis.
  • Gilbert syndrome: most common inherited disease associated with bilirubin glucuronidation. Unconjugated hyperbilirubinemia results from a UGT1A1 mutation. In contrast with HDFN, the baby has normal hematocrit, reticulocyte count, and peripheral smear.

References

  1. Calhoun, D. Postnatal diagnosis and management of hemolytic disease of the fetus and newborn. Retrieved March 14, 2021, from https://www.uptodate.com/contents/postnatal-diagnosis-and-management-of-hemolytic-disease-of-the-fetus-and-newborn.
  2. Dean, L. (2005). Blood Groups and Red Cell Antigens in Chapter 4 Hemolytic disease of the Newborn. National Center for Biotechnology Information, Bethesda, MD. Retrieved March 16, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK2266/
  3. Dulay, A. Erythroblastosis fetalis. Retrieved March 14, 2021, from https://www.merckmanuals.com/professional/gynecology-and-obstetrics/abnormalities-of-pregnancy/erythroblastosis-fetalis 
  4. Krywko, D., Yarrarapu, S., Shunkwiler, S. (2021). Kleihauer Betke Test. StatPearls. Retrieved March 14, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK430876
  5. Moise, K. (2020). RhD alloimmunization in pregnancy: Overview. UpToDate. Retrieved March 16, 2021, from https://www.uptodate.com/contents/rhd-alloimmunization-in-pregnancy-overview
  6. Moise, K. (2020). RhD alloimmunization in pregnancy: Management. UpToDate. Retrieved March 16, 2021, from https://www.uptodate.com/contents/rhd-alloimmunization-in-pregnancy-management
  7. Moise, K. (2020). RhD alloimmunization: Prevention in pregnant and postpartum patients. UpToDate. Retrieved March 16, 2021, from https://www.uptodate.com/contents/rhd-alloimmunization-prevention-in-pregnant-and-postpartum-patients
  8. Ross, M., de Alarcón, P. Hemolytic disease of the fetus and newborn. Neo Reviews. https://neoreviews.aappublications.org/content/14/2/e83

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