Type 2 Tissue-Specific Hypersensitivity (Second Mechanism): Hemolytic Disease of the Fetus and Newborn by Lila Abdelnour

Overview of Condition

e3b416d6df64488696fbaf5ad176f054_61768_1 — 2024-10-07 20:36:06 UTC

Hemolytic Disease of the Fetus and Newborn (HDFN) occurs when an Rh-negative mother produces IgG antibodies against Rh-positive fetal red blood cells following exposure during a previous pregnancy. In future pregnancies, these antibodies can cross the placenta and bind to the fetal Rh-positive red blood cells. This binding triggers the destruction of these cells, leading to anemia and potentially severe complications for the fetus. The immune response involved in HDFN is a classic example of Type 2 hypersensitivity, where antibodies specifically target antigens on cells, resulting in tissue damage. Understanding this mechanism is crucial for managing pregnancies at risk for HDFN and providing appropriate interventions to protect the fetus.

Risk Factors

e3b416d6df64488696fbaf5ad176f054_61768_1 — 2024-10-07 20:36:25 UTC

Risk factors for Hemolytic Disease of the Fetus and Newborn (HDFN) primarily include maternal Rh negativity and the presence of an Rh-positive fetus due to Rh incompatibility. This incompatibility can occur when Rh-positive blood cells from the fetus enter the mother's bloodstream, triggering her immune system to produce antibodies. A history of previous pregnancies with Rh-positive infants significantly increases the risk of sensitization in subsequent pregnancies.

Additionally, maternal factors such as advanced age, particularly over 35, a history of blood transfusions, and previous sensitization events like miscarriages involving Rh-positive blood also contribute to this risk. Socio-demographic factors, including certain ethnic backgrounds, may further influence the likelihood of encountering Rh incompatibility. Early detection through blood tests and proactive measures, such as administering Rho(D) immune globulin (RhoGAM), can help manage these risks effectively and improve outcomes for both the mother and the newborn.

Tissue/Organ Level Pathophysiology

e3b416d6df64488696fbaf5ad176f054_61768_1 — 2024-10-07 20:37:20 UTC

The mother's immune sensitization to the fetus's red blood cells causes anemia and triggers the excessive release of bilirubin, a byproduct of red blood cell breakdown. The fetus's liver struggles to eliminate the bilirubin, resulting in hyperbilirubinemia, which manifests as jaundice, characterized by a yellowing of the skin. Since newborns are less efficient at clearing bilirubin, it can accumulate in the blood, tissues, and fluids, worsening the condition. This increased workload enlarges the liver (hepatomegaly) as it attempts to clear the excess bilirubin. Similarly, the spleen enlarges (splenomegaly) as it filters out damaged red blood cells. To compensate for the rapid red blood cell destruction, the fetus's bone marrow, liver, and spleen increase red blood cell production, often releasing immature cells that cannot function properly. This overproduction further contributes to the enlargement of the liver and spleen. In severe cases, the anemia worsens, causing the heart to work harder, potentially leading to heart failure and fluid accumulation in tissues, known as hydrops fetalis, which puts additional strain on the heart. If left untreated, HDFN can lead to fatal complications, including kernicterus, a condition where bilirubin builds up in the brain, causing seizures, brain damage, or even death.

_{Reference: Sidbury, R. (2020).}_{Hemolytic disease of the fetus and newborn}_{. In StatPearls. StatPearls Publishing. Retrieved from}_{https://www.ncbi.nlm.nih.gov/books/NBK557423/}

Clinical Manifestations

e3b416d6df64488696fbaf5ad176f054_61768_1 — 2024-10-07 20:37:45 UTC

Clinical manifestations of Hemolytic Disease of the Fetus and Newborn (HDFN) can range from mild to severe. Common symptoms include jaundice, characterized by yellowing of the skin and eyes due to elevated bilirubin levels from hemolysis of red blood cells. Newborns may also exhibit anemia, leading to pallor and lethargy. In severe cases, hydrops fetalis can occur, resulting in excessive fluid accumulation in fetal compartments and potentially causing heart failure. Elevated bilirubin levels can lead to kernicterus, a form of neurological damage if untreated. Additionally, signs of cardiac distress, such as increased heart rate or decreased fetal movements, may be present

Does this condition conform to the traditional definition of the hypersensitivity type it is representing?

e3b416d6df64488696fbaf5ad176f054_61768_1 — 2024-10-07 20:38:27 UTC

Hemolytic disease of the fetus and newborn (HDFN) is a classic example of Type II hypersensitivity. This type of hypersensitivity involves the immune system attacking cells or tissues that the body recognizes as foreign, typically through the action of IgG or IgM antibodies. In HDFN the mother's immune system targets the fetus's red blood cells; typically due to Rh incompatibility. This is characteristic of Type II hypersensitivity, where the immune system targets specific cells or tissue. The mechanism involves antibody-mediated cytotoxicity where maternal antibodies bind to fetal red blood cells, leading to hemolysis (red blood cell destruction). This fits the classic model of Type II hypersensitivity where antibodies bind to cell-surface antigens and cause cell damage either by complement activation or by recruiting other immune cells. While this fits the traditional definition of Type II hypersensitivity, which involves antibody-mediated cytotoxicity against cell surface antigens, HDFN slightly differs in that it involves alloantigens (antigen from another individual of the same species) rather than an autoantigen (the body's own tissues). This nuanced distinction highlights that HDFN represents a hypersensitivity reaction but is driven by a maternal-fetal antigen mismatch. In this case, the immune response is against a foreign antigen, the fetal red blood cells expressing the Rh antigen.

References:

Sidbury, R. (2020). Hemolytic disease of the fetus and newborn. In StatPearls. StatPearls Publishing. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK557423/
Abbas, A. K., & Lichtman, A. H. (2017). Basic Immunology: Functions and Disorders of the Immune System (5th ed.). Elsevier.

Article on Hemolytic Disease of the Newborn

e3b416d6df64488696fbaf5ad176f054_61768_1 — 2024-10-07 20:39:29 UTC

Watch this video to learn more about HDN!

e3b416d6df64488696fbaf5ad176f054_61768_1 — 2024-10-07 20:51:01 UTC

Learn more about hypersensitivity type 2 reactions here!

e3b416d6df64488696fbaf5ad176f054_61768_1 — 2024-10-07 21:00:29 UTC

e3b416d6df64488696fbaf5ad176f054_61768_1 — 2024-10-07 21:04:53 UTC

e3b416d6df64488696fbaf5ad176f054_61768_1 — 2024-10-07 21:05:56 UTC

Article: "Hemolytic Disease of the Newborn"

estergomerta — 2024-10-08 04:35:07 UTC

Citation: Myle, A. K., & Al-Khattabi, G. H. (2021). Hemolytic Disease of the Newborn: A Review of Current Trends and Prospects. Pediatric health, medicine and therapeutics, 12, 491–498. https://doi.org/10.2147/PHMT.S327032

Article: Hemolytic disease of the fetus and newborn: managing the mother, fetus, and newborn.

estergomerta — 2024-10-08 13:44:57 UTC

Citation: Delaney, M., & Matthews, D. C. (2015). Hemolytic disease of the fetus and newborn: managing the mother, fetus, and newborn. Hematology, 2015(1), 146–151. https://doi.org/10.1182/asheducation-2015.1.146

Article: Hemolytic disease of the newborn.

estergomerta — 2024-10-08 14:25:22 UTC

Citation: MedlinePlus. (2023, December 31). Hemolytic disease of the newborn. MedlinePlus. https://medlineplus.gov/ency/article/001298.htm

Image: Hydrops fetalis

estergomerta — 2024-10-08 14:39:13 UTC

Citation: MedlinePlus. (n.d.). Image of a newborn with hemolytic disease. MedlinePlus. https://medlineplus.gov/ency/imagepages/19874.htm

Article: "Hemolytic disease"

estergomerta — 2024-10-08 15:00:14 UTC

Citation: Morgan Diagnostics. (2024, February 22). What is the Rh(D) immune globulin (RhoGAM) shot? Morgan Diagnostics. https://morgandiagnostics.com/what-is-the-rhod-immune-globulin-rhogam-shot/

Image

estergomerta — 2024-10-08 18:38:03 UTC

Image

estergomerta — 2024-10-08 18:38:48 UTC

jenniferaliturner — 2024-10-10 22:14:28 UTC

Citation: Hall, V., Vadakekut, E. S., & Avulakunta, I. D. (2024). Hemolytic Disease of the Fetus and Newborn. StatPearls. Retrieved October 12, 2024, from: https://www.ncbi.nlm.nih.gov/books/NBK557423/

jenniferaliturner — 2024-10-10 22:16:26 UTC

Citation: Medicosis Perfectionalis. (2018, May 29). Rh incompatibility and Hemolytic disease of the newborn (HDN) [Video]. YouTube. https://www.youtube.com/watch?v=0nOc-441XUI&t=201s

jenniferaliturner — 2024-10-10 22:18:40 UTC

Citation: Medicosis Perfectionalis. (2018, May 24). ABO Incompatibility-Hemolytic Disease Of The Newborn (HDN)- Hematology & Pathology. [Video]. YouTube. https://www.youtube.com/watch?v=t7THnrCOkEI&t=413s

Cellular Pathophysiology

jenniferaliturner — 2024-10-12 21:50:11 UTC

Hemolytic Disease of the Newborn (HDN) occurs primarily in two ways—ABO incompatibility and RH incompatibility between the mother’s blood and the fetus’ blood.

HDN caused by an ABO incompatibility can occur during a first pregnancy, such as when the mother has type O blood and the fetus has type A, B, or AB blood. The mother inherently expresses anti-A and anti-B, which tend to be IgG antibodies that can cross the placental barrier. Damage to the fetus’ red blood cells, however, is usually less severe due to this type of incompatibility. According to Hall et al., studies suggest this is either because fetal red blood cells present fewer ABO antigens than adults, or because other fetal body tissues also express ABO antigens and the red blood cells aren’t the only targets of IgG antibodies.

An Rh incompatibility can occur when the fetal blood cells present Rh-positive antigens and the mother’s blood cells present Rh-negative (Rh-) antigens.

HDN caused by an Rh incompatibility does not normally occur during a first pregnancy because the Rh-positive antibodies are typically IgM antibodies which cannot cross the placental barrier. However, during childbirth, the placenta is broken (fetomaternal hemorrhage) and the fetal and maternal blood often mixes resulting in the mother’s sensitization (alloimmunization). During subsequent pregnancies, if the fetus’ blood cells also present Rh-positive antigens, the mother’s immune system will remember the previous exposure and quickly forms IgG antibodies. Again, these IgG antibodies can pass through the placental barrier and attack the fetal blood cells.

This attack involves a process called agglutination. In agglutination, the IgG antibodies attach to the offending antigens on the fetal red blood cells, clumping them together. Macrophages recognize the Fc portion of the IgG antibodies and hemolysis occurs. The destroyed fetal red blood cells released unconjugated bilirubin into the blood stream which can overwhelm other organs, cross through the blood-brain barrier.

References:

Hall, V., Vadakekut, E. S., & Avulakunta, I. D. (2024). Hemolytic Disease of the Fetus and Newborn. StatPearls. Retrieved October 12, 2024, from: https://www.ncbi.nlm.nih.gov/books/NBK557423/

Medicosis Perfectionalis. (2018, May 24). ABO Incompatibility-Hemolytic Disease Of The Newborn (HDN)- Hematology & Pathology. [Video]. YouTube. https://www.youtube.com/watch?v=t7THnrCOkEI&t=413s

Medicosis Perfectionalis. (2018, May 29). Rh incompatibility and Hemolytic disease of the newborn (HDN) [Video]. YouTube. https://www.youtube.com/watch?v=0nOc-441XUI&t=201s

Therapeutic Management

jenniferaliturner — 2024-10-12 23:04:22 UTC

If Hemolytic Disease of the Newborn (HDN) is suspected during the pregnancy, a maternal fetal medicine specialist can monitor the fetal hemoglobin “every 2 weeks” and an intrauterine blood transfusion is an option if the hematocrit falls below 30% (Hall, 2024, Treatment/Management section, para. 8).

Treatment after birth depends on the severity of the condition. In mild cases of HDN, phototherapy may be enough to help the neonate get rid of excess bilirubin, but in more severe cases, blood transfusions, exchange transfusions, oxygen administration, and IV fluids may be necessary. Hydrops fetalis may also require ascites drainage, and a thoracentesis to treat pleural effusion in addition to the previously mentioned interventions.

HDN due to Rh incompatibility can be prevented in Rh-negative mothers, who have not been previously sensitized/alloimmunized, by an injection of Rh immunoglobin called RhoGAM. This injection prevents the mother’s antibodies from recognizing the fetus’ Rh-positive antigens, so hemolysis will not occur. RhoGAM is given approximately 28 weeks into the pregnancy, and if the fetus’ blood cells are Rh-positive, a second dose is given no more than 72 hours before birth (Hemolytic disease of the newborn (HDN). Stanford Health Care, 2024).

References:

Hall, V., Vadakekut, E. S., & Avulakunta, I. D. (2024). Hemolytic Disease of the Fetus and Newborn. StatPearls. Retrieved October 12, 2024, from: https://www.ncbi.nlm.nih.gov/books/NBK557423/

Stanford Children's Health. (2024). Hemolytic disease of the newborn (HDN). Stanford Health Care. https://www.stanfordchildrens.org/en/topic/default?id=hemolytic-disease-of-the-newborn-hdn-90-P02368