Rh Incompatibility in Pregnancy

By: Nathalie Antonios

An illustration of Rh incompatibility in pregnancyEditor's note: Sarah Walls created the above image for this article. You can find the full image and all relevant information here.

Rh incompatibility occurs when a pregnant woman whose blood type is Rh-negative is exposed to Rh-positive blood from her fetus, leading to the mother’s development of Rh antibodies. These antibodies have the potential to cross the placenta and attach to fetal red blood cells, resulting in hemolysis, or destruction of the fetus’s red blood cells. This causes the fetus to become anemic, which can lead to hemolytic disease of the newborn. In severe cases, an intrauterine blood transfusion for the fetus may be required to correct the anemia.

The first case involving Rh incompatibility was reported in 1939, although the Rh factor, a protein found on the surface of red blood cells, had not yet been discovered. This first case was reported by immunohematologist, Philip Levine and physician, Rufus Stetson, who published their case in The Journal of the American Medical Association. The authors presented an anonymous, twenty-five year old woman who checked into a local hospital during her thirty-third week of pregnancy complaining of labor pains and vaginal bleeding. The next day, she delivered an emaciated, stillborn fetus weighing only one pound and five ounces. The physicians had to expel the woman’s placenta to stop her from bleeding to death. The patient received a blood transfusion from her husband, as the two of them were of blood-type O. Ten minutes after completing the transfusion, the patient developed a chill and began feeling pain in her head and legs. When her vaginal bleeding resumed she was given a hysterectomy, followed by another blood transfusion from a different donor. Throughout her entire visit, the patient received transfusions from 104 Type O blood donors. Remarkably, the mother showed no blood transfusion reaction to twenty-one of those donors. Further tests indicated that the patient’s serum, or the plasma in the blood minus the clotting factors, specifically agglutinated her donors’ cells—or rather, 80 percent of all her blood transfusions.

The two physicians tried to discover what was causing the patient’s reaction. Initially, they believed that temperature was affecting agglutination in the patient’s blood, but they soon realized that temperature did not affect agglutination. The physicians reported that it was difficult to recreate these agglutinations for further testing since they still had not yet solved what was causing these isoimmunizations, or the development of antibodies in response to an antigenic stimulation.

It was not until a year later, Karl Landsteiner and Alexander S. Wiener coined the term “Rh factor” as the cause of the isoimmunization. They originally believed that Macacus rhesus, or Rhesus monkey, contained the same red blood cell surface antigen (Rh) as the one found in human red blood cells. This was soon proven wrong, as the composition of human sera and rhesus sera are different. Nonetheless, the term “Rh factor” has continued to be used to describe these human antigens, and the term “anti-Rh” is used to describe human antibodies formed against the Rh factor.

The most common form of Rh incompatibility occurs when an Rh-negative mother and an Rh-positive father produce an Rh-positive fetus. The situation does not become dangerous, however, until there is leakage from the fetal circulation into the maternal circulation. Once a significant amount of Rh-positive blood is released into the mother’s bloodstream, a process known as red-cell alloimmunization begins. This primary exposure of Rh-positive blood into the maternal circulation leads to sensitization, which results in the maternal production of Rh-positive antibodies called Rh immunoglobin G (IgG). The mother’s IgG antibodies may pass through the placenta and attack the fetal red blood cells inside the fetus since they are recognized as foreign.

The fetal effects of red-cell alloimmunization are known as hemolytic disease of the newborn, which is sometimes referred to as Rhesus disease. Once red-cell alloimmunization occurs, the IgG antibodies released into maternal circulation and the Rh-positive fetal red blood cells bind to form antigen-antibody complexes. These complexes are initiated for destruction, resulting in alloimmune-induced hemolytic anemia. Although the Rh blood group system is comprised of several antigens (i.e., D, C, c, E, e) - the Rh D antigen accounts for the majority of all cases involving Rh incompatibility since it is the most immunogenic. Once red blood cells are broken down, they produce bilirubin, which causes an infant to become jaundiced.

In the majority of cases, sensitization occurs during delivery, and even then, Rh-positive firstborn infants are usually not affected. The process of sensitization trains the body to have a response to future antigens; in this case the Rh factor present in the fetus’s red blood cells. After sensitization, it takes time for the mother to develop Rh antibodies against the fetal blood and for her antibodies to equilibrate in the fetus’s circulation. Because of the sensitization process, firstborn infants are usually not affected by the mother’s sensitization, unless she has been sensitized through previous a miscarriage or abortion. If the mother has not been sensitized before the delivery, the mother does not produce enough IgG antibody response during delivery, leaving the firstborn unharmed.

The risk and severity of sensitization response increases with each subsequent pregnancy involving an Rh positive fetus. Without treatment, women who have increased effects of Rh incompatibility may produce a mildly anemic second child. Subsequent births, however, may result in fetal death due to severe antibody-induced hemolytic anemia. This most extreme form of Rh incompatibility is what occurred in the first reported agglutination case in 1939.

Prevention remains the best treatment for Rh incompatibility. Since the antibody Rh IgG, or RhoGAM, was first released in 1968, it has been remarkably successful in decreasing Rh incompatibility. The administration (injection) of this antibody, was originally referred to as “Big D” in blood-banking circles and was made from the plasma of other Rh-positive mothers who had given birth to an Rh-positive child. Women who had usually high concentrations of “Big D” were reported to have made up to 80,000 dollars a year for selling their plasma. Nonetheless, the commercial production of this antibody has reduced the risk of Rh incompatibility from 10 to 20 percent to less than 1 percent. The antibody is administered whenever there is a chance of Rh-positive fetal cells entering the maternal circulation of an Rh-negative mother. When indicated, it is normally administered at 28 to 32 weeks of pregnancy and again within 72 hours after delivery. Threatening or spontaneous miscarriage, amniocentesis, or chorionic villus sampling results may also indicate the need for administration of RhoGAM.

The exact mechanism of how RhoGAM works is still unknown and it is only used for preventing Rh disease. Once sensitization has occurred in the mother, RhoGAM is not effective in preventing the progression of the disease. Once the affected infant is born, aggressive hydration and phototherapy using bilirubin lights can be used as treatment against jaundice. In severe cases, an intrauterine blood transfusion may be required while the fetus remains in the uterus. In order to correct the fetus’ anemia, this procedure involves a needle directed into the umbilical cord under ultrasound guidance. The transfusions take place every two to three weeks through the remainder of the pregnancy.


  1. Advent, Neil, and Marion Reid. “The Rh Blood Group System: A Review,” Blood 95 (2000): 375–87.
  2. Dodd, J. M., Windrim, R. C., van Kamp, I. L. “Techniques of Intrauterine Fetal Transfusion for Women with Red-Cell Isoimmunisation for Improving Health Outcomes (Review),” The Cochrane Collaboration (2010).
  3. Lee, Kimberly and David Zieve. “Rh Incompatibility,” MD Consult (2009). http://www.mdconsult.com.ezproxy1.lib.asu.edu/das/patient/body/238755736-5/1142260880/10041/31860.html (Accessed November 1, 2010).
  4. Levine, Philip, Newark, N. J, and Stetson, Rufus. “An Unusual Case of Intra-Group Agglutination,” The Journal of the American Medical Association (1939): 126–27.
  5. Starr, Douglas. “Blood: An Epic History of Medicine and Commerce.” In The Blood Boom, 210–11. New York: Harper Collins Publishers, 2002.


How to cite

Antonios, Nathalie, "Rh Incompatibility in Pregnancy". Embryo Project Encyclopedia ( ). ISSN: 1940-5030 https://hdl.handle.net/10776/2073


Arizona State University. School of Life Sciences. Center for Biology and Society. Embryo Project Encyclopedia.

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