Pathophysiology

The pathophysiology of Hemolytic Disease of the Fetus and Newborn (HDFN) is a classic example of immunology in action, where the mother’s immune system inadvertently harms the fetus or newborn. Understanding how this happens is key to prevention and treatment

The Core Problem

HDFN occurs when maternal IgG antibodies, specific for antigens present on fetal/newborn red blood cells (RBCs) but absent on maternal RBCs, cross the placenta and cause destruction of the fetal/newborn RBCs

Here’s the step-by-step breakdown of the pathophysiology:

Prerequisite: Antigen Incompatibility & Maternal Sensitization (Alloimmunization)

• Incompatibility: The fundamental requirement is that the fetus must inherit a red blood cell antigen from the father that the mother lacks. The most famous example is an RhD-negative mother carrying an RhD-positive fetus. Other common examples involve ABO incompatibility (Group O mother, Group A or B fetus) or antibodies to other blood group antigens like Kell (K), Duffy (Fy^a), Kidd (Jk^a), c, E, etc
• Sensitization Event: The mother’s immune system must be exposed to the foreign fetal RBC antigen. This usually happens through Fetal-Maternal Hemorrhage (FMH), where small amounts of fetal RBCs leak across the placenta into the maternal circulation
  • Timing: While FMH can occur anytime during pregnancy, the largest volumes typically occur during delivery. It can also happen during miscarriage, abortion, ectopic pregnancy, amniocentesis, chorionic villus sampling (CVS), or abdominal trauma
  • Prior Transfusion: Less commonly, sensitization can occur if the mother previously received a transfusion of blood positive for the antigen she lacks (e.g., an RhD-negative woman transfused with RhD-positive blood years before pregnancy)
• Immune Response (Primary): When the mother’s immune system encounters the foreign fetal antigen for the first time, it mounts a primary immune response
  • APCs present the antigen to T helper cells, which activate B cells
  • Initially, IgM antibodies are produced. IgM is large and does not cross the placenta, so it typically doesn’t harm the fetus in this first sensitizing pregnancy (unless sensitization happened very early)
  • Crucially, class switching occurs, leading to the production of IgG antibodies, and long-lived memory B cells specific for the fetal antigen are generated

Subsequent Pregnancy with an Antigen-Positive Fetus: The Anamnestic Response

• Re-exposure: If the mother becomes pregnant again with a fetus positive for the same antigen, even a tiny FMH (which is almost inevitable) will re-expose her immune system to the antigen
• Secondary (Anamnestic) Response: The memory B cells are rapidly activated. This results in a faster, stronger production of high-titer IgG antibodies specific for the fetal antigen

Placental Transfer of Maternal IgG

• Mechanism: IgG is the only immunoglobulin class actively transported across the placenta. This occurs via specific Fc receptors (FcRn) on placental cells (syncytiotrophoblasts)
• Consequence: The harmful maternal IgG antibodies are efficiently delivered into the fetal circulation

Antibody Binding and Red Cell Destruction in the Fetus (Hemolysis)

• Binding: Maternal IgG antibodies circulate in the fetus and bind specifically to the corresponding antigen on the fetal RBC membrane
• Mechanism of Destruction: The primary mechanism is Extravascular Hemolysis
  • Opsonization: The IgG-coated fetal RBCs are recognized by Fc receptors on phagocytic cells (macrophages) within the fetal Mononuclear Phagocyte System (MPS), primarily located in the spleen and, to a lesser extent, the liver
  • Phagocytosis: These macrophages engulf and destroy the antibody-coated RBCs
  • (Complement Role): While some IgG subclasses (IgG1, IgG3) can activate complement, leading potentially to C3b deposition (further opsonization) or rarely intravascular lysis (MAC formation), the dominant mechanism in HDFN is Fc-mediated phagocytosis in the spleen

Fetal Consequences of Hemolysis

• Anemia: Progressive destruction of RBCs leads to fetal anemia. The severity depends on the amount and specificity of the maternal antibody, the antigen density on fetal cells, and the fetus’s ability to compensate
• Compensatory Erythropoiesis: The fetus attempts to compensate for the anemia by increasing RBC production (erythropoiesis)
  • Bone Marrow: Production increases significantly
  • Extramedullary Hematopoiesis: If anemia is severe, RBC production also occurs outside the bone marrow, primarily in the liver and spleen. This causes these organs to enlarge (hepatosplenomegaly)
  • Erythroblastosis Fetalis: Increased erythropoiesis leads to the release of immature RBC precursors, including nucleated red blood cells (NRBCs or erythroblasts), into the fetal circulation. This gives the disease its older name
• Bilirubin Production: The breakdown of hemoglobin from destroyed RBCs releases large amounts of bilirubin
  • Fetal Clearance: In utero, unconjugated bilirubin crosses the placenta into the maternal circulation, where it is efficiently conjugated and excreted by the mother’s liver. Therefore, significant jaundice is typically NOT seen in the fetus itself.
• Hydrops Fetalis: This is the most severe form of fetal HDFN, characterized by excessive fluid accumulation in tissues and body cavities (ascites, pleural effusion, pericardial effusion, skin edema)
  • Mechanism: A combination of factors resulting from severe, chronic anemia:
    • High-Output Cardiac Failure: The fetal heart works harder to deliver oxygen with fewer RBCs, eventually failing
    • Hypoproteinemia: Decreased plasma protein (especially albumin) production by the damaged/overworked liver (due to extramedullary hematopoiesis and hypoxic damage) reduces plasma oncotic pressure
    • Increased Capillary Permeability: Possibly due to hypoxia
  • Hydrops fetalis often leads to fetal death if not treated aggressively in utero (e.g., with intrauterine transfusions)

Neonatal Consequences (After Birth)

• Transition: At birth, the placental “lifeline” for bilirubin removal is severed
• Hyperbilirubinemia (Neonatal Jaundice): This becomes the major problem after birth
  • Ongoing Hemolysis: Maternal IgG antibodies persist in the newborn’s circulation for weeks to months, continuing to destroy neonatal RBCs
  • Immature Liver: The newborn’s liver has limited capacity to conjugate bilirubin (due to low levels of the enzyme UDP-glucuronosyltransferase)
  • Accumulation: The combination of increased bilirubin production (from hemolysis) and decreased conjugation/excretion leads to a rapid rise in unconjugated bilirubin levels in the newborn’s blood
• Kernicterus (Bilirubin Encephalopathy)
  • Mechanism: Unconjugated bilirubin is lipid-soluble and can cross the immature blood-brain barrier. If levels become excessively high, it deposits in brain tissues, particularly the basal ganglia
  • Consequence: This deposition is toxic to neurons, causing permanent neurological damage, developmental problems, hearing loss, or even death. This is the most feared neonatal complication of HDFN and the primary reason for treating neonatal hyperbilirubinemia (e.g., with phototherapy or exchange transfusion)
• Persistent Anemia: Even after bilirubin levels are controlled, the ongoing destruction of RBCs by persistent maternal IgG can cause anemia in the first few weeks or months of life, potentially requiring simple RBC transfusions

Antigen Specificity Matters

• Anti-D: Historically caused the most severe HDFN, often leading to hydrops. Incidence drastically reduced by Rh Immune Globulin (RhIG)
• Anti-K (Kell): Can cause severe HDFN, not only by hemolysis but also because the Kell antigen is present on early erythroid precursors, so anti-K can suppress fetal erythropoiesis, worsening the anemia
• ABO HDFN: Most common type overall (usually group O mother with A or B baby). Typically much milder than Rh or other blood group HDFN. Often presents only as neonatal jaundice, rarely requires intrauterine treatment. Milder because: (1) fetal A/B antigens are less developed; (2) A/B antigens are widely distributed on other tissues, absorbing some maternal antibody; (3) much of maternal anti-A/anti-B is IgM, which doesn’t cross the placenta (though IgG components do)

Key Terms

• Alloimmunization (Sensitization): The process by which an individual produces an immune response (antibodies) against foreign antigens from the same species (e.g., mother against fetal antigens)
• Fetal-Maternal Hemorrhage (FMH): The leakage of fetal blood cells into the maternal circulation
• Anamnestic Response: The rapid and enhanced secondary immune response upon re-exposure to an antigen, mediated by memory cells
• Placental Transfer: The active transport of maternal IgG antibodies across the placenta into the fetal circulation via FcRn receptors
• Extravascular Hemolysis: Destruction of antibody-coated red blood cells by phagocytic cells (macrophages) in the spleen and liver
• Opsonization: Coating of cells with antibodies (or complement) to enhance phagocytosis
• Erythropoiesis: The production of red blood cells
• Extramedullary Hematopoiesis: Blood cell production occurring outside the bone marrow (e.g., in the liver and spleen)
• Hepatosplenomegaly: Enlargement of the liver and spleen
• Erythroblastosis Fetalis: The presence of excessive numbers of nucleated red blood cells (erythroblasts) in the fetal circulation due to severe hemolysis
• Hydrops Fetalis: Severe, abnormal accumulation of fluid in fetal tissues and body cavities, usually due to severe anemia and heart failure
• Hyperbilirubinemia: Excessively high levels of bilirubin in the blood, causing jaundice
• Kernicterus (Bilirubin Encephalopathy): Neurological damage caused by the deposition of unconjugated bilirubin in the brain tissue of newborns