Rh Disease - History of Medical Advances in Rh Disease

History of Medical Advances in Rh Disease

The Rhesus blood type was first discovered in 1937 by Karl Landsteiner and Alexander S. Wiener.

In 1939 Philip Levine and Rufus E. Stetson published their findings about a family who had a stillborn baby who died of hemolytic disease of the newborn. The mother was aged 25 and it was her second pregnancy and she suffered blood loss at the delivery. Both parents were blood group O and the husband's blood was used to give the mother a blood transfusion, but the mother suffered a severe transfusion reaction. They investigated this transfusion reaction. Since the mother and the father were both blood group O, they concluded that there must be a previously undiscovered blood group antigen that was present on the husband's RBCs but was not present on the mother's RBCs and that the mother had formed antibodies against the new blood group antigen. This suggested for the first time that a mother could make blood group antibodies because of immune sensitization to her fetus's RBCs. They did not name this blood group antigen, but it was subsequently found to be the Rhesus factor.

The first treatment for Rh disease was an exchange transfusion, which was invented by Dr. Alexander S. Wiener. That procedure was further refined by Dr, Harry Wallerstein, a transfusionist. Although the most effective method of treating the problem at the time, it was only partially ameliorative in cases where damage to the neonate had already been done. Children with severe motor damage and/or retardation could result. However, it is estimated that in the two decades it was used approximately 200,000 lives were saved, and the great majority were not brain damaged.

Ronald Finn, in Liverpool, England applied a microscopic technique for detecting fetal cells in the mother's blood. It led him to propose that the disease might be prevented by injecting the at-risk mother with an antibody against fetal red blood cells. He proposed this for the first time to the public on February 18, 1960. A few months later, he proposed at a meeting of the British Genetical Society that the antibody be anti-RhD.

Nearly simultaneously with him, William Pollack, then of Ortho Pharmaceutical Corporation, and researchers John Gorman and Vincent Freda of New York City's Columbia-Presbyterian Medical Center, having come to the same realization, set out to prove it by injecting a group of male prisoners at Sing Sing Correctional Facility with antibody provided by Ortho, obtained by a fractionation technique developed by Dr Pollack (who also provided Dr. Finn with several vials of antibody during a visit by Dr. Finn to Ortho).

Animal studies had previously been conducted by William Pollack, using a rabbit model of Rh. This model, named the rabbit HgA-F system, was a perfect animal model of human Rh, and enabled Dr. Pollack's team to gain experience in preventing hemolytic disease in rabbits by giving specific HgA antibody, as was later done with Rh-negative mothers. One of the needs was a dosing experiment that could be used to determine the level of circulating Rh-positive cells in an Rh-negative pregnant female derived from her Rh-positive fetus. This was first done in the rabbit system, but subsequent human tests at the University of Manitoba conducted under Dr. Pollack's direction confirmed that this result matched the human dosing perfectly. The dose is 20 µG of antibody for 1mL of Rh-positive red cells.

Sir William Liley performed the first successful intrauterine transfusion in 1963.

Dr. Gorman's sister-in-law was the first at risk woman to receive a prophylactic injection on January 31, 1964. Clinical trials set up by Dr. Pollack in 42 clinical centers in the US, Great Britain, Germany, Sweden, Italy, and Australia confirmed their hypothesis, and the vaccine was finally approved in England and the United States in 1968. The FDA approved the drug under the name RhoGAM, with a fixed dose of 300 µG, to be given within three days postpartum. There being no known harm done by delaying the dosage for a week or more after birth, Ortho asked the FDA to grant permission for it to be given without a postpartum time restriction. In addition, Dr. John M. Bowman, one of the researchers at the University of Manitoba, and Dr Freda pushed to allow antepartum use. All of this was subsequently granted. Within a year or so, the antibody had been injected with great success into more than 500,000 women. Time magazine picked it as one of the top ten medical achievements of the 1960s. By 1973, it was estimated that in the US alone, over 50,000 babies' lives had been saved. The use of Rh immune globulin to prevent the disease in babies of Rh negative mothers has become standard practice, and the disease, which used to claim the lives of 10,000 babies each year in the US alone, has been virtually eradicated in the developed world. The achievement was made almost entirely without support from the NIH, who rejected the New York group's proposal twice. The group got instead only a small grant ($329,765 over 10 years) from the City of New York. The total cost of the effort was only a couple of million dollars, which is about the cost of the life-time care of a half-dozen irreparably brain-damaged children. In 1980, Prof Cyril Clarke, Dr Ronald Finn, Dr John Gorman, Dr Vincent Freda, and Dr William Pollack each received an Albert Lasker Award for Clinical Medical Research for their work on Rhesus blood types and the prevention of Rh disease.

Two of the Canadian researchers from the University of Manitoba, Dr. Bruce Chown and Dr. John M. Bowman, licensed a version of the vaccine, known as WinRho SD, in 1980. The drug is sold in 35 countries by the Manitoba-based research firm Cangene, listed on the Toronto Stock Exchange with worth of about $175 million. Cangene was purchased by the Winnipeg Rh Institute, a facility founded by Chown and Bowman and dedicated to conducting research into blood related diseases. Dr. Chown is honored by the Canadian Medical Hall of Fame for his lifelong work with erythroblastosis fetalis.