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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.

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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.

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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

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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

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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/

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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

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

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

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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.

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Article on Hemolytic Disease of the Newborn 

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Article on Hemolytic Disease of the Newborn 

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Hemolytic disease of the newborn (HDN) is a blood problem in newborns. It occurs when your baby’s red blood cells break down at a fast rate. It’s also called erythroblastosis fetalis.

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Watch this video to learn more about HDN!

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Watch this video to learn more about HDN!

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Hemolytic Disease of the Newborn (HDN), Animation

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Learn more about hypersensitivity type 2 reactions here! 

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Learn more about hypersensitivity type 2 reactions here! 

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Hypersensitivity Type II (Cytotoxic reaction) - causes, pathophysiology,  complement system

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Article: "Hemolytic Disease of the Newborn"

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Article: "Hemolytic Disease of the Newborn"

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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

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Hemolytic Disease of the Newborn: A Review of Current Trends and Prospects - PubMed

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Hemolytic disease of the newborn (HDN), also known as Erythroblastosis fetalis, is a hemolytic condition that predominantly affects rhesus-positive fetuses and infants born to rhesus-negative mothers. The pathophysiology of HDN begins with maternal antibodies attacking fetal red blood cells f …

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

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

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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

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doi: 10.1182/asheducation-2015.1.146.

Affiliations

¹ Seattle Children's Hospital, Seattle, WA; University of Washington, Seattle, WA; and Bloodworks NW, Seattle, WA.

² Seattle Children's Hospital, Seattle, WA; University of Washington, Seattle, WA; and.

doi: 10.1182/asheducation-2015.1.146.

Affiliations

¹ Seattle Children's Hospital, Seattle, WA; University of Washington, Seattle, WA; and Bloodworks NW, Seattle, WA.

² Seattle Children's Hospital, Seattle, WA; University of Washington, Seattle, WA; and.

Abstract

Hemolytic disease of the fetus and newborn (HDFN) affects 3/100 000 to 80/100 000 patients per year. It is due to maternal blood group antibodies that cause fetal red cell destruction and in some cases, marrow suppression. This process leads to fetal anemia, and in severe cases can progress to edema, ascites, heart failure, and death. Infants affected with HDFN can have hyperbilirubinemia in the acute phase and hyporegenerative anemia for weeks to months after birth. The diagnosis and management of pregnant women with HDFN is based on laboratory and radiographic monitoring. Fetuses with marked anemia may require intervention with intrauterine transfusion. HDFN due to RhD can be prevented by RhIg administration. Prevention for other causal blood group specificities is less studied.

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Hemolytic disease of the fetus and newborn: managing the mother, fetus, and newborn - PubMed

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Hemolytic disease of the fetus and newborn (HDFN) affects 3/100 000 to 80/100 000 patients per year. It is due to maternal blood group antibodies that cause fetal red cell destruction and in some cases, marrow suppression. This process leads to fetal anemia, and in severe cases can progress to edema ...

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Hemolytic disease of the newborn: MedlinePlus Medical Encyclopedia

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Hemolytic disease of the newborn (HDN) is a blood disorder in a fetus or newborn infant. In some infants, it can be fatal.

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What Is The Rho(D) Immune Globulin (Rhogam) Shot?

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Rho(D) Immune Globulin, also known as “Rhogam”, is a shot which expectant Rh-negative mothers receive in order to prevent HDN.

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Citation: MedLab Study Hall. (n.d.). Hemolytic disease of the fetus and newborn (HDFN). MedLab Study Hall. Retrieved October 8, 2024, from https://medlabstudyhall.com/hdfn/

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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/

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Hemolytic Diseases of the Newborn - StatPearls - NCBI Bookshelf

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Hemolytic disease of the fetus and newborn (HDFN) is an immune-mediated red blood cell (RBC) disorder in which maternal antibodies attack fetal or newborn RBCs.[1][2] HDFN can cause significant morbidity and mortality, especially in limited healthcare resource settings. Effects of HDFN range from mi…

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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

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Rh incompatibility and Hemolytic disease of the newborn (HDN)

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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

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ABO Incompatibility - Hemolytic Disease Of The Newborn (HDN) - Hematology & Pathology