- The Science Behind the Miracle
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The Science Behind the Miracle

SOLVING THE MYSTERY OF HDN

Many years prior to the FDA approval of RhoGAM® Brand Rho(D) Immune Globulin (Human), a pregnant patient was being admitted to Bellevue Hospital in New York City 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 husband's type O (apparently compatible) blood.1

An unknown antibody
What occurred next would lead Dr. Philip Levine and associates to define the pathogenesis of hemolytic disease of the newborn (HDN). The patient experienced a transfusion reaction. Subsequent studies a month later by Levine and Stetson showed incompatibility with 80% of 104 of the same ABO type bloods cross-matched with her serum. It was then that researchers realized that an unknown antibody was present.

In their studies, Levine and Stetson 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 The investigators 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 cross-match 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.


Researching the Rh factor
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 Burnham2 proposed that maternal sensitization to the Rh factor is due to an antigen that crosses the placental barrier into the maternal circulation.6 Based on these discoveries, in 1960 two research groups (Finn and Clarke et al. in England and Freda, Gorman, and Pollack in the United States) independently embarked on programs to prevent Rh sensitization by passive immunization with an Rh antibody.


THE DEVELOPMENT OF RHOGAM® BRAND

In 1964, 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 began the first human trials of a new anti-sensitization agent with a single female patient at New York’s Columbia Presbyterian Hospital. By 1966, they happily reported the first successful prevention of maternal sensitization to the Rh factor by the administration of anti-Rho(D) preparation following delivery7.

RhoGAM® Brand is born…
On May 29, 1968—only hours after the initial batch of RhoGAM® Brand Rho(D) Immune Globulin (Human) was approved by the U.S. Food and Drug Administration—the first dose of RhoGAM® Brand was administered to a new mother at Holy Name Hospital in Teaneck, New Jersey. That mom, Marianne Cummins, would later safely give birth to two healthy sons, all thanks to the protective properties of RhoGAM® Brand.


…and generations of newborns are saved
Since the introduction of RhoGAM® Brand, HDN has been virtually eliminated in the developed world. This remarkable achievement is due not only to the efficacy of the product, but also to the reliability of its manufacturer, Ortho Clinical Diagnostics. In 40 years of manufacturing, there has never been an interruption in the RhoGAM® Brand product supply.


Timeline to a miracle

  • 1939: Dr. Philip Levine and Dr. Rufus Stetson publish a paper showing that baby-mother incompatibility is the cause of hemolytic disease of the newborn (HDN).


  • 1944: Dr. Levine joins Ortho to continue his breakthrough research into the mechanics of the Rh system.


  • 1950: Ortho introduces The Coombs Test to identify sensitized Rh-negative patients.


  • 1960: Drs. John Gorman, Vincent Freda (Columbia University), and Dr. William Pollack (Ortho Research Foundation) embark on a program to prevent Rh sensitization by immunizing patients with an Rh antibody.


  • 1964: The three doctors begin the first female clinical trials at Columbia Presbyterian Hospital in New York City.


  • 1966: Gorman, Freda, and Pollack report the first successful prevention of maternal sensitization to the Rh factor by the administration of anti-Rho(D) preparation following delivery.


  • 1968: RhoGAM® Brand Rho(D) Immune Globulin (Human), the first drug proven to prevent HDN, is introduced. The first shipment is loaded onto a delivery truck 10 minutes after the U.S. Food and Drug Administration grants approval. A short time later, an Rh-negative woman in nearby Teaneck, New Jersey becomes the first RhoGAM® Brand recipient. She went on to have two more healthy children.


  • 1977: The first mini-dose, MICRhoGAM® Brand Rho(D) Immune Globulin (Human) is introduced in the marketplace.


  • 1984: Antepartum protocols are recommended by the American College of Obstetricians and Gynecologists as a result of ongoing studies.


  • 1985: Pre-filled syringes of RhoGAM® and MICRhoGAM® Brand Rho(D) Immune Globulin (Human) are introduced in the marketplace.


  • 1997: RhoGAM® and MICRhoGAM® Ultra-Filtered Rho(D) Immune Globulin (Human) are introduced in the marketplace.


  • 2001: Ortho Clinical Diagnostics enhances the safety of RhoGAM® Brand by removing the latex components and preservatives from its formulation and adding safety shields to its syringes — the first U.S. company to do so.


  • 2006: Ortho Clinical Diagnostics adds barcodes to the labels on RhoGAM® Brand and MICRhoGAM® Brand syringes.


  • 2007: Ortho Clinical Diagnostics introduces RhoGAM® and MICRhoGAM® Ultra-Filtered PLUS Rho(D) Immune Globulin (Human).



References:

  1. Levine P. The History of Rh and Hemolytic Disease of the Newborn. Symposium on RhoGAM® Rho(D) Immune Globulin (Human). New York, NY, April 17, 1969.
  2. Levine P, Katzin EM, Burnham L. Isoimmunization in pregnancy: its possible bearing on the etiology of erythroblastosis fetalis. JAMA. 1941;116:825-827.
  3. Levine P. Serological factors as possible causes in spontaneous abortions. J Hered. 1943;34:71.
  4. Levine P. and Stetson RE. Unusual cases of intragroup agglutination. JAMA. 1939;113:126.
  5. Landsteiner K, Wiener AS. Agglutinable factor in human blood recognized by immune sera for rhesus blood. Proc Soc Exp Biol Med. 1940;43:223.
  6. Queenan, John T. Cornell Medical Center, Symposium on RhoGAM Proceedings, April 17, 1969.
  7. Freda VJ, Gorman J, Pollack W. Rh factor: Prevention of iso-immunization and clinical trial on mothers. Science. 1966;151:828.