Hemolytic Disease of the Fetus and Newborn (HDFN)

Hemolytic disease of the fetus and newborn (HDFN), also known as erythroblastosis fetalis, is a rare immune-mediated red blood cell (RBC) disorder in which a mismatch between mother and fetus causes maternal antibodies to attack fetal or newborn RBCs.¹ This destruction of fetal or neonatal RBCs by maternal immunoglobulin G (IgG) antibodies results in hemolysis, anemia, and the release of bilirubin.²

Etiology and Subtypes

The primary cause of HDFN is the incompatibility of maternal and fetal blood group antigens. Many blood group systems can be involved in HDFN, including ABO, Rhesus, Kell, and Kidd. However, Rhesus factor incompatibility is linked to more severe cases of HDFN.²

Two primary mechanisms underlie the targeting of fetal/neonatal RBC antigens. The first mechanism is ABO incompatibility, which is a congenital mismatch between fetal and maternal blood types that occurs in approximately 15% to 25% of pregnancies. The second mechanism is alloimmunization due to fetomaternal hemorrhage (FMH), which is an acquired immune-mediated mechanism that more frequently occurs in subsequent pregnancies rather than the pregnancy in which the FMH happened; it is caused by the development of maternal antibodies after exposure to fetal blood. The antigen most commonly involved in FMH is Rhesus D, and the immune reaction is triggered in RhD-negative mothers following exposure to RhD-positive fetal blood. Other antigens, however, are involved in approximately 1.5% to 2.5% of pregnancies.^1,2

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Epidemiology

The incidence of HDFN significantly decreased from 1% to 0.5% of all newborns worldwide after the introduction of anti-Rh(D) immunoprophylaxis. The antepartum administration of anti-Rh(D) immunoprophylaxis further decreased the incidence to 0.1%.¹ However, the disease remains a concern, particularly when incompatibility between maternal and fetal blood group antigens is not managed appropriately. ABO incompatibility remains the single most frequent cause of HDFN.²

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Signs and Symptoms

A common manifestation of fetal HDFN is anemia, which can progress to cause severe edema, hydrops fetalis, and death.³ Decreased fetal movements and echogenic bowels are also observed.⁴

In neonates, signs and symptoms include anemia, neutropenia, and thrombocytopenia. Anemia can cause lethargy, skin pallor, and alterations in heart rhythm. Hyperbilirubinemia may also be reported and can lead to jaundice.^1,3,4

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Complications

Anemia in HDFN can result in several complications, including high-output cardiac failure/myocardial ischemia and hydrops fetalis when fluid accumulates in at least 2 extravascular compartments. Excessive accumulation of bilirubin in the infant brain may become chronic and result in kernicterus, which is characterized by cerebral palsy, auditory dysfunction, paralysis of upward gaze, and permanent intellectual dysfunction.^1,2

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Diagnosis

The diagnosis of HDFN involves a combination of clinical assessment and laboratory testing.¹ Pregnant women should be tested to determine their blood group and Rh status. Indirect antiglobulin testing should also be performed to detect IgG antibodies.³

The maternal history can guide prenatal care and identify a pregnancy in which the fetus is at risk for HDFN due to maternal alloimmunization. Fetal ultrasound is indicated to determine gestational age and confirm the absence of ascites.³

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Treatment

The treatment of HDFN involves a multidisciplinary approach and includes exchange transfusions, phototherapy, and anti-Rh(D) immunoglobulin immunoprophylaxis.^1,5

Exchange transfusion is a risky and invasive procedure in which the neonate’s blood is replaced with compatible donor blood to reduce bilirubin levels and address anemia.^5,6 In phototherapy, which is used to treat neonatal jaundice, specialized light converts bilirubin to a form that can be eliminated by the body in urine or stool.¹ The need for maternal immunoprophylaxis is evaluated at 28 weeks of gestation, after delivery, and during FMH events. The recommendation is to administer prophylaxis to a pregnant woman if she tests Rh(D)-negative and is carrying a fetus who tests Rh(D)-positive at 28 and 34 weeks of gestation.¹

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Prognosis

With early and appropriate management, the overall prognosis for a fetus or newborn with HDFN is good and has significantly improved. Severe cases and delays in care can still lead to long-term complications, such as permanent neurologic dysfunction; however, prophylaxis and advances in medical interventions, including intrauterine transfusions, have led to better outcomes for affected infants.^1,2 

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References

1. Hall V, Avulakunta ID. Hemolytic diseases of the newborn. StatPearls [Internet]. Updated November 22, 2022. Accessed August 23, 2023.
2. Nassar GN, Wehbe C. Erythroblastosis fetalis. StatPearls [Internet]. Updated June 26, 2023. Accessed August 23, 2023.
3. Delaney M, Matthews DC. Hemolytic disease of the fetus and newborn: managing the mother, fetus, and newborn. Hematology. 2015;2015(1):146-151. doi:10.1182/ash-education-2015.1.146
4. Hemolytic disease of the fetus and newborn/maternal alloimmunization. Fetal Health Foundation. Accessed August 23, 2023.
5. Reverberi R, Reverberi L. Removal kinetics of exchange transfusion. Blood Transfus. 2007;5(2):93-101. doi:10.2450/2007.0018-07
6. Ree IMC, Besuden CFJ, Wintjens VEHJ, et al. Exchange transfusions in severe Rh‐mediated alloimmune haemolytic disease of the foetus and newborn: a 20‐year overview on the incidence, associated risks and outcome. Vox Sang. 2021;116(9):990-997. doi:10.1111/vox.13090

Reviewed by Kyle Habet, MD, on 8/28/2023.

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Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.