Hemolytic fetal disease of the newborn (HDN)

What is hemolytic disease of the newborn (HDN)?

Hemolytic Disease of the Newborn (HDN), also known as Erythroblastosis Fetalis, is a condition where a fetus’ red blood cells are destroyed by maternal antibodies. This occurs when the mother and baby have incompatible blood types, typically involving the Rh factor or ABO blood group system.

How does hemolytic disease of the newborn (HDN) happen?

HDN most commonly occurs when an Rh-negative mother has an Rh-positive baby. However, it can also occur when the mother and baby have different ABO blood types

Naturally occurring antibodies occur in the plasma of subjects who lack the corresponding antigen and who have not been transfused or been pregnant. The most important are anti-A and anti-B. They are usually IgM and react optimally at cold temperatures also known as cold antibodies. Immune antibodies develop in response to the introduction of red cells possessing antigens that the subject lacks through transfusion or by transplacental passage during pregnancy. These antibodies are commonly IgG, although some IgM antibodies may also develop usually in the early phase of an immune response. Immune antibodies react optimally at 37oC. Only IgG antibodies are capable of transplacental passage from mother to foetus as IgM is too big. The most important immune antibody is the anti-D. These antibodies can cross the placenta and attack the baby’s red blood cells, causing them to break down. 

In hemolytic disease of the newborn, the mother is Rh-negative while the father is Rh-positive. The Rh factor is a protein that is found on the surface of red blood cells. The Rh blood group locus is composed of 2 related structural genes, RhD and RhCE, which encode the membrane proteins that carry the D, Cc and Ee, antigens. The RhD gene may be either present or absent, giving the Rh D+ or Rh D- phenotype, respectively. During the first pregnancy, leakage of D+ fetal red cells across the placenta results in the mother becoming immunised against the D antigen as this antigen is not naturally occurring but is produced after sensitization as the fetus is Rh-positive. However, the amount of anti-D antibody that crosses the placenta into the fetal circulation following the initial exposure is too low to cause hemolysis. During subsequent pregnancies, the mother mounts an anamnestic immunological response to D+ fetal red cells if the fetuses inherit the Rh-positive antigen from the father unless the father is heterozygous for the D antigen and there is a 50% probability that the fetus may be Rh-negative. The IgG alloantibody produced by the mother is small enough to cross through the placenta into the fetal circulation and binds to fetal RBCs that are D+. The IgG-sensitized fetal RBCs are cleared from the circulation by macrophages in the foetal spleen. This leads to anemia and hyperbilirubinemia.

What are the signs and symptoms of hemolytic disease of the newborn (HDN)?

The severity of HDN can vary from mild to severe. Mild cases of HDN may cause no symptoms, while severe cases can be life-threatening. The severity of HDN depends on the number of antibodies that the mother has produced and the amount of time that the baby has been exposed to the antibodies. 

In severe cases of HDN, the baby’s red blood cells can be destroyed so quickly that the baby cannot produce new red blood cells fast enough to keep up. This can lead to anemia. In addition to anemia, severe cases of HDN can also cause other complications, such as jaundice, hepatosplenomegaly and edema. Jaundice is a yellowing of the skin and eyes that is caused by the breakdown of red blood cells. Hepatosplenomegaly is an enlargement of the liver and spleen. Edema is swelling of the body caused by fluid retention. In the most severe cases of HDN, the baby can develop heart failure or die before birth. 

How is hemolytic disease of the newborn (HDN) tested?

HDN is usually diagnosed based on the results of a blood test. The blood test will check the fetus’ blood type, Rh factor and antibody levels. The physician may also request for a complete blood count (CBC) and a bilirubin level. 

In laboratory diagnosis, the peripheral blood smear shows normochromic normocytic anemia with the presence of numerous nucleated RBCs and occasional spherocytes. DAT is positive due to the presence of antibodies and there is increased serum bilirubin and LDH with a decrease in haptoglobin level. 

How is hemolytic disease of the newborn (HDN) treated?

The treatment of HDN depends on the severity of the condition. Mild cases of HDN may not require any treatment. More severe cases of HDN may require phototherapy (light therapy) or blood transfusions. 

Phototherapy is a treatment that uses special UV lights to help the baby’s body get rid of bilirubin. Bilirubin is a byproduct of the breakdown of red blood cells. High levels of bilirubin can damage the baby’s brain (kernicterus). 

Blood transfusions are a treatment that involves replacing the baby’s blood with blood from a donor. Blood transfusions are necessary if the baby’s anemia is severe or if the baby is developing other complications, such as heart failure. Exchange transfusion can remove circulating bilirubin and antibody-coated RBCs, replacing them with RBCs compatible with maternal serum and providing albumin with new bilirubin binding sites. The process is time consuming and labour intensive but remains the ultimate treatment to prevent kernicterus.

In some cases, HDN can be prevented by giving the mother an injection of Rh immunoglobulin (RhIg) during pregnancy. RhIg is a medication that helps to prevent the mother’s immune system from producing antibodies against the baby’s Rh-positive blood cells. 

If a woman is  pregnant and Rh-negative, the physician will test the woman’s  blood to see if she has been sensitized to Rh-positive blood cells. If she has not been sensitized, she will be given an injection of RhIg at 28 weeks of pregnancy and again after delivery. 

Key Points of hemolytic disease of the newborn (HDN)


An allo-immune hemolytic anemia in the fetus or newborn. This is due to a fetal-maternal incompatibility for one of the red cell blood group systems i.e. Rh group causing maternal IgG to cross the placenta and attach to fetal red cells which will be destroyed by the reticuloendothelial system. 

ABO and Rh Blood group systems

Most important system in transfusion and organ transplantation medicine.
Incompatible transfusion → acute intravascular hemolysis, renal failure and death
Gene located in chromosome 9
A & B are co-dominant, O is recessive
Anti RhD can cause hemolytic transfusion reactions
Gene located in chromosome 1
Rh positive – gene is present, Rh negative – gene is absent
Autosomal recessive inheritance pattern

Pathophysiology of hemolytic disease of the newborn

Hemolytic disease of the newborn, Rh incompatibility, ABO incompatibility, hemolysis, anemia
At the heart of HDN lies Rh incompatibility, a condition that arises when an Rh-negative mother carries an Rh-positive fetus. During the first pregnancy, maternal exposure to fetal Rh-positive red blood cells through placental microtransfusion can lead to sensitization, where the mother’s immune system develops antibodies against Rh-positive antigens. In subsequent pregnancies, these Rh antibodies can cross the placenta and attack the fetal red blood cells, resulting in hemolysis. The anamnestic response, a phenomenon observed in second and subsequent pregnancies, refers to the enhanced antibody production by the sensitized mother.

Clinical features

  • Intrauterine death in severe cases
  • Anemia
  • Jaundice
  • Edema
  • Hepatosplenomegaly
  • Kernicterus

Laboratory investigations of hemolytic disease of the newborn

Peripheral blood characteristics

Peripheral blood smear: Normochromic normocytic anemia with numerous nucleated red blood cells and occasional spherocytes

Other important investigations and expected results

  • DAT positive
  • ↑ serum bilirubin
  • ↑ LDH
  • ↓ haptoglobin

Treatment and management

For Rh HDN

  • Exchange transfusion if necessary
  • RhD prophylaxis in RhD negative mothers


  • Mild severity
  • May be seen in first pregnancy
  • Usually blood group O mothers with blood group A or B infants
  • Phototherapy as treatment

Disclaimer: This article is intended for informational purposes only and is specifically targeted towards medical students. It is not intended to be a substitute for informed professional medical advice, diagnosis, or treatment. While the information presented here is derived from credible medical sources and is believed to be accurate and up-to-date, it is not guaranteed to be complete or error-free. See additional information.


  1. Anemia: Diagnosis and Treatment (Willis, 2016).
  2. Management of Anemia: A Comprehensive Guide for Clinicians (Provenzano et al., 2018)
  3. Goldberg S, Hoffman J. Clinical Hematology Made Ridiculously Simple, 1st Edition: An Incredibly Easy Way to Learn for Medical, Nursing, PA Students, and General Practitioners (MedMaster Medical Books). 2021.

Related Diseases

Serologic Crossmatching

Serologic Crossmatching

Introduction  A serological crossmatch, also known as a blood compatibility test, is a vital procedure performed before a blood transfusion to ensure compatibility between the donor's red blood cells and the recipient's serum or plasma. In the realm of blood...

Indirect Antiglobulin (Coombs) Test (IAT)

Indirect Antiglobulin (Coombs) Test (IAT)

Introduction The indirect antiglobulin test (IAT), also known as the indirect Coombs test, plays a crucial role in ensuring safe and compatible blood transfusions. This vital laboratory procedure delves into the world of antibodies, protecting against potentially...

Direct Antiglobulin (Coombs) Test (DAT)

Direct Antiglobulin (Coombs) Test (DAT)

Introduction The direct antiglobulin test (DAT), also known as the Coombs test, is a crucial tool in diagnosing immune-mediated red blood cell (RBC) destruction. This test detects the presence of antibodies or complement proteins bound to the surface of RBCs,...