RhoGam: The triumph of Medical Science over Rh disease

Expectant mothers have their blood routinely “typed” by a laboratory early in their pregnancies. The different blood types, A, B, AB, and O, are accompanied by the designation “positive” or “negative.” What does this designation mean, and why is it an important health concern?

Red blood cell membranes have proteins attached to them. One of the best studied of these is the Rh protein, named for the rhesus monkey, the animal used in the initial research. Considering all ethnicities combined, about 80 percent of humans have this protein and are “Rh positive.” This is genetically determined. The humans lacking this protein are “Rh negative.”

The Rh protein has been extensively researched because it is able to incite a strong immune system response. If a red blood cell with the Rh protein were to “accidentally” enter the blood stream of a person that was Rh negative, then that person’s immune system would classify the protein as a foreign substance, or ANTIGEN, and the type B lymphocytes would produce ANTIBODIES, molecules that bind to the Rh protein, and cause its destruction and removal from the circulation.

The first antibodies to be made are very large molecules that function for a few weeks. They are then supplanted by very small antibodies called IgG antibodies, which persist in low numbers in the blood permanently.  In addition, a population of antibody producing cells often called “memory cells” are formed. These remain “at the ready” to churn out millions of IgG antibodies to the Rh protein if it is ever found in the bloodstream again. This immune sensitization is called “Rh isoimmunization.”

A pregnant woman may become isoimmunized if she is Rh negative and her fetus is Rh positive. Fetal red blood cells can enter the maternal circulation any time in pregnancy or during the delivery process. The mother can then develop antibodies to the Rh protein. Since the first antibodies formed are large molecules, they cannot cross the placenta into the fetal circulation if they develop during the first pregnancy, and the firstborn child seldom suffers any harm.

If the same patient has a second pregnancy with a fetus that is Rh positive, her primed immune system produces small IgG antibodies that can cross the placenta and attack the red blood cells of the fetus causing their breakdown and destruction, resulting in “hemolytic disease of the newborn.” Affected infants can suffer from profound anemia, brain damage from high levels of bilirubin (a chemical released after red blood cells are destroyed), seizure disorders, jaundice, and in some cases, fetal death.

Although modern medical management treatments exist to prevent poor outcomes in affected pregnancies, the best strategy is to prevent isoimmunization from ever happening. Researchers in the late 1950’s discovered a way to do this.

The Rh antigen was discovered in 1939.  About the same time, a case study was published about a mother whose second pregnancy resulted in a stillborn baby. The mother, who happened to have blood type O, was transfused with her husband’s blood, also type O, after excessive post-delivery bleeding.  She had a massive transfusion reaction. The doctors concluded that she must have had antibodies to something on the husband’s red cells. This was later found to be the Rh protein.

An English researcher in the late 1950’s proposed that hemolytic newborn disease might be preventable if the mother was injected with antibodies. These antibodies in circulation might block her immune system from preventing the development of the memory cells and block permanent antibody production. He proposed to the British Genetical Society that this antibody should be anti-Rh.

The Americans were not far behind. Researchers from Ortho Pharmaceutical Corporation, along with Columbia Presbyterian Medical Center in New York, devised an experiment to prove that this would work. They injected a group of male prisoners at Sing Sing with Rh antibodies and then exposed them to the Rh protein. The experiment overwhelmingly showed that permanent antibody formation could be prevented by giving “temporary antibodies,” which is today called RhoGam. These antibodies eliminated the immune response.

These antibodies, in injectable form, were marketed as “RhoGam” and approved by the F.D.A. in 1968. Time Magazine hailed it as one of the top ten medical achievements of the 1960’s.

Today, RhoGam is routinely given in the early, third trimester of pregnancy and at delivery (if the baby is Rh positive) to Rh negative women. Hemolytic disease of the newborn, which formerly claimed the lives of ten thousand babies each year in the United States, has now been virtually eliminated in the developed world. Fortunately, if isoimmunization (antibody formation) does occur, these pregnancies can, for the most part, be managed with modern treatment options to promote successful outcomes.