The Rhesus (Rh) blood group system is crucial in clinical medicine, second only to the ABO system. The Rh system includes over 50 antigens on the surface of red blood cells. The D antigen is the most significant because of its high capacity to provoke an immune reaction (immunogenicity). The presence or absence of the D antigen determines an individual’s Rh status, which has profound implications for blood transfusions and pregnancy. Understanding this marker is fundamental to preventing severe medical complications.
Defining the Rh Factor and D Antigen
The D antigen is a protein structure on the surface of red blood cells and is the defining component of the Rh factor. An individual is classified as Rh-positive if the D antigen is present (about 85% of the population) and Rh-negative if their red blood cells entirely lack it.
The production of the D antigen is governed by the RHD gene, which resides on chromosome 1. People who are Rh-positive have at least one functional copy of the RHD gene, while Rh-negative individuals typically have a non-functional or deleted copy of this gene. Unlike the ABO blood group, where individuals naturally produce antibodies against the antigens they lack, Rh-negative people do not naturally possess anti-D antibodies.
Instead, an Rh-negative person must be actively sensitized, meaning their immune system must first be exposed to Rh-positive red blood cells to produce anti-D antibodies. Sensitization occurs through an incompatible blood transfusion or during pregnancy. Once exposed to the foreign D antigen, the immune system mounts a long-lasting response by creating anti-D antibodies.
Implications for Blood Transfusion
Due to the D antigen’s high immunogenicity, blood banks strictly adhere to Rh matching protocols. The rule is that Rh-negative patients should only receive Rh-negative blood components. If an Rh-negative patient receives Rh-positive blood, the D antigen is recognized as foreign, triggering the recipient’s immune system to produce anti-D antibodies.
While the initial incompatible transfusion may not cause an immediate reaction, the patient becomes sensitized. If the patient later receives a second transfusion of Rh-positive blood, anti-D antibodies rapidly bind to and destroy the donor red blood cells. This immune-mediated destruction is a serious and potentially fatal hemolytic transfusion reaction.
Blood products for Rh-negative recipients are selected to lack the D antigen. In rare emergencies where Rh-negative blood is unavailable, Rh-positive blood may be given to Rh-negative males or post-childbearing females. This decision is made knowing it will likely cause sensitization, complicating future transfusions. This practice is strictly avoided for females of childbearing potential due to the risk it poses to any future Rh-positive fetus.
D Antigen and Hemolytic Disease of the Fetus and Newborn
The most serious consequence of D antigen incompatibility occurs in pregnancy, leading to Hemolytic Disease of the Fetus and Newborn (HDFN). This develops when an Rh-negative mother carries an Rh-positive fetus, which inherits the D antigen from the father. Although maternal and fetal blood systems usually remain separate, small amounts of fetal red blood cells can enter the mother’s circulation, most often during delivery.
Fetal red blood cells may also cross the placenta during events such as miscarriage, ectopic pregnancy, abdominal trauma, or prenatal procedures like amniocentesis. Once the Rh-negative mother is exposed to the Rh-positive fetal red blood cells, her immune system perceives the D antigen as a threat and begins to produce anti-D antibodies. This process is called alloimmunization or sensitization.
These initial anti-D antibodies are typically produced late in the first pregnancy or at delivery, so the first Rh-positive fetus is usually unaffected. Once the mother is sensitized, her immune system retains a memory of the D antigen. In a subsequent pregnancy with another Rh-positive fetus, her immune system rapidly produces large quantities of Immunoglobulin G (IgG) anti-D antibodies.
IgG antibodies are small, allowing them to cross the placenta into the fetal bloodstream. Once inside the fetus, these maternal anti-D antibodies attach to the D antigens on the fetal red blood cells, marking them for destruction. The resulting breakdown of red blood cells (hemolysis) causes fetal anemia, which can range from mild to severe.
The fetal body attempts to compensate by increasing red blood cell production, but this often fails. Severe anemia can lead to hydrops fetalis, where extensive fluid accumulation occurs, often resulting in death before or shortly after birth. For newborns who survive, the massive breakdown of red blood cells releases high levels of bilirubin, causing severe jaundice and potentially permanent neurological damage if not promptly treated.
Management of Rh Incompatibility
Modern management of Rh incompatibility focuses on prevention, which has dramatically reduced the incidence of HDFN. This approach centers on the use of Rh Immunoglobulin (RhIg), often known as RhoGAM. RhIg is a purified blood product containing ready-made anti-D antibodies.
When RhIg is injected into an Rh-negative mother, the circulating anti-D antibodies bind to any Rh-positive fetal red blood cells that entered her bloodstream. This binding neutralizes the fetal cells by clearing them from the mother’s circulation before her own immune system can recognize the D antigen and mount a lasting response. The administered antibodies are temporary and decay over time.
Standard protocol involves giving RhIg prophylaxis to Rh-negative mothers around the 28th week of pregnancy. This antepartum dose provides protection throughout the third trimester, when the risk of fetomaternal hemorrhage increases. A second dose is administered within 72 hours of delivery if the newborn is determined to be Rh-positive.
RhIg is also administered after any event that could cause fetal-maternal blood mixing, such as miscarriage, abortion, or external trauma. RhIg is a preventative measure only and is not effective if the mother has already been sensitized and developed permanent anti-D antibodies. Regular prenatal screening for anti-D antibodies ensures the strategy remains effective and allows for specialized monitoring if sensitization has occurred.