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The History of Hemolytic Disease of the Newborn (HDN) [also known as Hemolytic Disease of the Fetus and Newborn (HDFN)] and RhoGAM®
Many years prior to the FDA approval of RhoGAM® Rho(D) Immune Globulin (Human), a pregnant patient was being admitted to Bellevue Hospital for high blood pressure and albuminuria. In her 33rd week of pregnancy, labor pains and vaginal bleeding were recorded in the absence of fetal heart sounds. Shortly thereafter, the patient delivered a stillborn fetus. To control bleeding, the type O patient was given a transfusion of her type O husband's (apparently compatible) blood.1
After receiving her husband's blood, what occurred next would lead to defining the pathogenesis of hemolytic disease of the newborn by Dr. Philip Levine and associates. The patient experienced a transfusion reaction. Subsequent studies a month later by Levine and Stetson, showed incompatibility with 80 percent of 104 of the same ABO type bloods crossmatched with her serum. It was then that researchers realized the presence of an unknown antibody. In these studies, they observed that the reactions were just as active at 37ºC and room temperature. Two months later, the antibody was much weaker, and a year later, all activity disappeared.2 They correctly theorized that the mother had been immunized by the cells of the fetus, which had inherited an antigen from the father that was foreign to the mother.3 In this historic case, the mother had been sensitized to the D antigen and produced anti-D. The anti-D crossed the placenta and caused the death of the fetus. The anti-D was not detectable in the slide or uncentrifuged tube crossmatch with her husband's Rh-positive red cells. Transfusion with her husband's Rh-positive blood resulted in destruction of the Rh-positive incompatible red cells (transfusion reaction) and stimulated an increased production of anti-D. One month later, the quantity of anti-D was so great that it was detectable by the direct agglutination techniques (slide and uncentrifuged tube) available at that time. |
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In 1939, Levine and Stetson published their study4 indicating an atypical agglutinin in this patient's blood. In 1940, Landsteiner and Wiener discovered the Rh factor on the red blood cell.5 In 1941, Levine, Katzin, and Burnham6 proposed that maternal sensitization to the Rh factor is due to an antigen that crosses the placental barrier into the maternal circulation.7
Based on these discoveries, two research groups (Finn and Clarke et al. in England and Freda, Gorman and Pollack in the United States) in 1960 independently embarked on programs to prevent Rh sensitization by passive immunization with Rh antibody.
In 1966, Freda, Gorman and Pollack reported the first successful prevention of maternal sensitization to the Rh factor by the administration of anti-Rho(D) preparation following delivery.8
In 1968, ORTHO launched RhoGAM® Rho(D) Immune Globulin (Human) to prevent HDN. RhoGAM® was the result of years of collaborative work by Dr. John G. Gorman and Dr. Vincent Freda at Columbia University in New York and Dr. William Pollack at Ortho Research Foundation in Raritan, New Jersey.
Charles Lockwood, MD, the current Chair of the American College of Obstetricians and Gynecologists' Committee on Obstetric Practice, has described the introduction of RhoGAM® as "one of the greatest accomplishments in ob-gyn in the past 50 years.
Now and Then
1939: Dr. Philip Levine and Dr. Rufus Stetson published a paper in the Journal of the American Medical Association describing an atypical agglutinin in the blood of a woman who had just given birth to a stillborn fetus and subsequently suffered a hemolytic reaction when transfused with her husband's blood.
1940: Landsteiner and Weiner discovered the Rh factor.
1941: Drs. Levine, Katzin and Burnham proposed that maternal sensitization to the Rh factor is due to an antigen that crosses the placental barrier into the maternal circulation causing HDN.
1944: Dr. Levine joined ORTHO to continue his breakthrough research into the mechanics of the Rh system in human blood. 
1960: Drs. Gorman, Freda and Pollack embarked on a program to prevent Rh sensitization by passive immunization with Rh antibody.
1961: A larger study was initiated with male volunteers.
1964: First female clinical trials began at Columbia Presbyterian Hospital.
1966: Drs. Freda, Gorman and Pollack reported the successful prevention of maternal sensitization to the Rh factor by the administration of anti-Rho(D) preparation following delivery.
1968: Introduced RhoGAM® Rho(D) Immune Globulin (Human), the first drug developed to prevent Rh hemolytic disease of the newborn. The first shipment was in trucks 10 minutes after receiving FDA approval, allowing an Rh negative woman to be the first recipient of RhoGAM® Rho(D) Immune Globulin (Human). She went on to have two more healthy children.
1977: Introduced MICRhoGAM® Rho(D) Immune Globulin (Human), the first mini-dose.
1985: Introduced RhoGAM® Rho(D) Immune Globulin (Human) pre-filled syringes.
1997: Introduced RhoGAM® Ultra-Filtered Rho(D) Immune Globulin (Human).
2001: Introduced RhoGAM® Ultra-Filtered Rho(D) Immune Globulin (Human) in pre-filled syringes with latex-free safety shields in U.S., the first company to do so. Additionally, RhoGAM® is manufactured free of any mercury or mercury containing substances such as thimerosal.
2007: Introduced RhoGAM® Ultra-Filtered PLUS Rho(D) Immune Globulin (Human).
1Levine P. The History of Rh and Hemolytic Disease of the Newborn. Symposium on RhoGAM® Rho(D) Immune Globulin (Human) held in New York City, NY, April 17, 1969.
2Levine P, Katzin EM, Burnham L. Isoimmunization in pregnancy: its possible bearing on the etiology of erythroblastosis fetalis. JAMA. 1941;116:825-827.
3Levine P. Serological factors as possible causes in spontaneous abortions. J Hered. 1943;34:71.
4Levine P. and Stetson RE. Unusual cases of intragroup agglutination. JAMA. 1939;113:126.
5Landsteiner K. and Wiener AS. Agglutinable factor in human blood recognized by immune sera for rhesus blood. Proc Soc Exp Biol Med. 1940;43:223.
6Levine P, Katzin EM, and Burnham L. Iso-immunization in pregnancy: its possible bearing on erythroblastosis fetalis, JAMA.1941;116:825.
7Queenan, John T. Cornell Medical Center, Symposium on RhoGAM® Proceedings, April 17, 1969.
8Freda VJ, Gorman J, and Pollack W. Rh factor: Prevention of iso-immunization and clinical trial on mothers. Science 1966;151:828.
9Harmening DM. Modern Blood Banking and Transfusion Practices 4th Edition. Baltimore: F A Davis 1999.
Complete Prescribing Information for RhoGAM® Ultra-Filtered PLUS |