Hemolytic Disease of the Fetus and Newborn (HDFN)

Hemolytic disease of the fetus and newborn (HDFN), also known as erythroblastosis fetalis, is an immune-mediated blood disorder affecting fetuses and neonates in which the mother’s immune system produces antibodies that attack and destroy fetal or neonatal red blood cells (hemolysis).^1,2 The etiology of HDFN involves 2 factors: incompatibility of the mother’s and baby’s erythrocytes and fetomaternal hemorrhage.¹

Erythrocyte Incompatibility

The 2 primary forms of erythrocyte incompatibility that cause HDFN involve ABO blood type and rhesus (Rh) factor mismatches.^1,2 

In the United States between 1996 and 2010, approximately 78.1% of cases of HDFN were caused by ABO incompatibility, whereas only 4.3% of cases in the United States during this period were due to Rh(D) incompatibility, likely because of the introduction of postpartum and antepartum Rh(D) prophylaxis. The remaining 17.6% of HDFN cases were due to maternal production of antibodies against minor antigens.³

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Usually, ABO incompatibility occurs when mothers with group O blood type have babies with group A or B blood type; however, ABO incompatibility results in less severe HDFN symptoms than Rh(D) incompatibility.² The Rh antigen most commonly involved in the etiology of HDFN is the D antigen, although other Rh antigens, including c, C, E, and e antigens, may also contribute to pathogenesis.⁴

Maternal antibodies that have less commonly been reported to cause HDFN include those against Kell (K, k, Kp^a, Kp^b, Js^a, Js^b), Duffy (Fy^a and Fy^b), Kidd (Jk^a), MNS (M, N, S, and s), Diego, Lutheran, Ge, Go, Jr^a, Ku, P, U, and Xg antigens. ^2,5-9

These antigens on fetal erythrocytes are inherited on paternal genes, resulting in a mismatch between baby and mother.¹

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Maternal Alloimmunization Due to Fetomaternal Hemorrhage

Antigens on the surface of fetal erythrocytes come into contact with the maternal immune system, which then produces antibodies against the fetal antigens, perceived as “non-self.”¹⁰ The mixing of maternal and fetal blood is called fetomaternal hemorrhage. The Kleihauer Betke test is used to determine the amount of fetomaternal blood mixing and whether anti-Rh(D) prophylaxis is required.¹

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Maternal blood group alloantibodies from the immunoglobulin (Ig) G1 and IgG3 subclasses cause hemolysis more effectively than alloantibodies from other the IgG subclasses, with more clinically significant manifestations of HDFN. After the second trimester of pregnancy, the neonatal Fc receptor (FcRn), the major histocompatibility complex (MHC) class I-related neonatal receptor, transports maternal immunoglobulins, especially IgG1 and IgG3, across the placenta to the fetus.^6,11 

Once the maternal IgG antibodies circulate within the fetal blood, they bind to antigen-positive fetal red blood cells, which the fetal spleen removes from the circulation via hemolysis. Maternal immune-mediated destruction of the erythrocytes results in fetal or neonatal anemia and subsequent hyperbilirubinemia. Excess bilirubin accumulates as a byproduct of the metabolism of free hemoglobin from destroyed erythrocytes.⁶ Anemia and hyperbilirubinemia, particularly that due to unconjugated bilirubin, can contribute to a host of HDFN-related complications, including fetal or neonatal mortality.^6,10

Read more about HDFN complications

Mixing can also occur when fetal erythrocytes enter the maternal circulation and maternal antibodies are produced against incompatible fetal antigens. According to the American College of Obstetricians and Gynecologists, the degree of fetomaternal hemorrhage is sufficient to contribute to maternal alloimmunization in only approximately 15% to 50% of pregnancies (as little as 0.1 mL of fetal blood enters the maternal circulation).¹

Obstetric events (eg, ectopic pregnancy, miscarriage, spontaneous or therapeutic early termination of pregnancy, maternal blood transfusion, invasive prenatal testing including amniocentesis and chorionic villus sampling, cesarean section delivery, placental abruption, other bleeding during pregnancy, toxemia, hydrops fetalis or HDFN in a previous pregnancy) increase the risk for fetomaternal hemorrhage and the development of HDFN in subsequent pregnancies.^1,12 

The maternal immune system develops an immunological memory, preserving antibodies against the baby’s red blood cell antigens in case of another exposure to the antigen. In subsequent pregnancies, the maternal immune system is then likely to produce additional antibodies, causing yet more severe manifestations of HDFN.¹⁰ 

Read more about HDFN risk factors

References

1. Hall V, Avulakunta ID. Hemolytic diseases of the newborn. StatPearls [Internet]. Updated November 22, 2022. Accessed September 1, 2023.
2. Nassar GN, Wehbe C. Erythroblastosis fetalis. StatPearls [Internet]. Updated June 26, 2023. Accessed September 1, 2023.
3. Yu D, Ling LE, Krumme AA, Tjoa ML, Moise KJ. Live birth prevalence of hemolytic disease of the fetus and newborn in the United States from 1996 to 2010. AJOG Glob Rep. 2023;3(2):100203. doi:10.1016/j.xagr.2023.100203
4. Dean L. Hemolytic disease of the newborn. In: Blood Groups and Red Cell Antigens. Bethesda, MD: National Center for Biotechnology Information (US); 2005. 
5. Moise KJ. Fetal anemia due to non-Rhesus-D red-cell alloimmunization. Semin Fetal Neonatal Med. 2008;13(4):207-214. doi:10.1016/j.siny.2008.02.007
6. 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/asheducation-2015.1.146
7. Fung MK, Grossman BJ, Hillyer CD, Westhoff CM. Technical manual, 18th edition. Association for the Advancement of Blood & Biotherapies; 2014.
8. Anti-K, anti-k, anti-Kpa and anti-Kpb. Atlas Medical. Accessed September 1, 2023.
9. Fives KR, Chism DA, Beetz B, Elkins I, Butala M. Hemolytic disease of the fetus and newborn due to anti-Gonzales antibody. Cureus. 2023;15(3). doi:10.7759/cureus.36860
10. Myle AK, Al-Khattabi GH. Hemolytic disease of the newborn: a review of current trends and prospects. Pediatric Health Med Ther. 2021;12:491-498. doi:10.2147/PHMT.S327032
11. Firan M, Bawdon R, Radu C, et al. The MHC class I-related receptor, FcRn, plays an essential role in the maternofetal transfer of gamma-globulin in humans. Int Immunol. 2001;13(8):993-1002. doi:10.1093/intimm/13.8.993
12. Nandyal RR. Hemolytic disease of the newborn. J Hematol Thrombo Dis. 2015;3:2. doi:10.4172/2329-8790.1000203

Reviewed by Hasan Avcu, MD, on 9/11/2023.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.