Hemolytic disease of the fetus and newborn

Last updated: May 4, 2023

Summarytoggle arrow icon

Hemolytic disease of the fetus and newborn (HDFN) is a condition characterized by the destruction of fetal red blood cells (RBC) and subsequent anemia. It is commonly caused by a Rhesus (Rh) or ABO incompatibility between the mother and fetus, although other blood incompatibilities (e.g., Kell blood group incompatibility) and other conditions not caused by red cell alloimmunization (e.g., congenital heart defects) can also cause HDFN. In Rh incompatibility, maternal IgG antibodies form after maternal exposure to fetal Rh-positive blood during birth or pregnancy-related complications (e.g., fetomaternal hemorrhage). The initial pregnancy is not affected; however, subsequent pregnancies are at risk of fetal hemolysis and, in severe cases, intrauterine hydrops fetalis. ABO incompatibility, on the other hand, may lead to fetal hemolysis in the first pregnancy because of preexisting antibodies in the mother, and it usually has a milder course of disease. Newborns may present with pallor, jaundice, and hepatosplenomegaly. Diagnosis of HDFN involves clinical and laboratory assessment for evidence of antibody-mediated hemolysis (e.g., Coombs test). Prenatal imaging may be used to exclude hydrops fetalis. Treatment includes iron supplementation and, in the case of severe jaundice, phototherapy. In rare cases, extremely low hemoglobin (Hb) levels require transfusion of red cell concentrates. Since Rh incompatibility may be fatal, anti-D immunoglobulin prophylaxis is administered to Rh-negative pregnant women. ABO incompatibility, on the other hand, rarely presents with complications and does not require immunoglobulin prophylaxis.

Definitiontoggle arrow icon

HDFN is a condition characterized by blood group incompatibility between the mother and fetus that leads to the destruction of fetal erythrocytes by maternal antibodies.

Etiologytoggle arrow icon


Pathophysiologytoggle arrow icon

ABO incompatibility

Rh incompatibility

Kell blood group system incompatibility [4][5]

Subtypes and variantstoggle arrow icon

Nonimmune hydrops fetalis [7]

Clinical featurestoggle arrow icon



ABO incompatibility usually has a significantly milder course of disease than Rh incompatibility.

Anemia may conceal cyanosis.

Diagnosticstoggle arrow icon

The diagnosis of HDFN requires evidence of hemolysis in the presence of fetomaternal blood incompatibility.

Prenatal diagnosis

Postnatal diagnosis

Differential diagnosestoggle arrow icon

ABO vs. Rh incompatibility

ABO incompatibility

Rh incompatibility

  • Common
  • Rare
Disease during the first pregnancy
  • Common
  • Rare

Clinical symptoms

  • Generally normal to mild; may be asymptomatic
  • Mild to severe

Coombs test (direct or indirect)

  • Weak positive or negative
  • Positive
  • Present
  • Rare

Differential diagnoses of petechiae in newborns

Neonatal alloimmune thrombocytopenia


The differential diagnoses listed here are not exhaustive.

Treatmenttoggle arrow icon


Preventiontoggle arrow icon


Anti-D immunoglobulin (RhoGAM)


Referencestoggle arrow icon

  1. Benrubi GI. Handbook of Obstetric and Gynecologic Emergencies. Lippincott Williams & Wilkins ; 2010
  2. Basu S, Kaur R, Kaur G. Hemolytic disease of the fetus and newborn: current trends and perspectives. Asian J Transfus Sci. 2011; 5 (1): p.3-7.doi: 10.4103/0973-6247.75963 . | Open in Read by QxMD
  3. Kliegman R, Stanton B, St. Geme J, Schor N. Nelson Textbook of Pediatrics. Elsevier ; 2015
  4. Vaughan JI, Manning M, Warwick RM, Letsky EA, Murray NA, Roberts IAG. Inhibition of Erythroid Progenitor Cells by Anti-Kell Antibodies in Fetal Alloimmune Anemia. N Engl J Med. 1998; 338 (12): p.798-803.doi: 10.1056/nejm199803193381204 . | Open in Read by QxMD
  5. Dean L. Blood Groups and Red Cell Antigens, Chapter 8 The Kell blood group. Bethesda (MD): National Center for Biotechnology Information (US) ; 2005
  6. Snowise S, Moise KJ. Haemolytic Disease of the Fetus and Newborn. Elsevier ; 2019: p. 484-496.e3
  7. Temple R, Bull K. Petechiae in a Newborn.. American family physician. 2015; 92 (11): p.1017-8.
  8. Bellini C, Hennekam RC. Non-immune hydrops fetalis: A short review of etiology and pathophysiology. Am J Med Genet A. 2012; 158A (3): p.597-605.doi: 10.1002/ajmg.a.34438 . | Open in Read by QxMD
  9. Vanaparthy R, Mahdy H. Hydrops Fetalis. StatPearls. 2021.
  10. Kirpalani H, Whyte RK, Andersen C, et al.. The Premature Infants in Need of Transfusion (PINT) study: a randomized, controlled trial of a restrictive (low) versus liberal (high) transfusion threshold for extremely low birth weight infants. J Pediatr. 2006; 149 (3): p.301-307.doi: 10.1016/j.jpeds.2006.05.011 . | Open in Read by QxMD
  11. Committee on Practice Bulletins—Obstetrics. Practice Bulletin No. 181: Prevention of Rh D Alloimmunization 2017. Obstet Gynecol. 2017; 130 (2): p.e57-e70.doi: 10.1097/aog.0000000000002232 . | Open in Read by QxMD
  12. $Kleihauer Betke Test.
  13. Strutz J, Mann W, Schumacher K. Praxis der HNO-Heilkunde, Kopf- und Halschirurgie. Thieme Verlag (2009) ; 2009

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