RhoGAM at 50: A Drug Still Saving Lives of Newborns

Rh disease has essentially been eradicated in high-income countries but until the late 1960s was one of the most severe and devastating conditions for newborns, killing approximately 10,000 infants a year and causing brain damage in many more in the United States alone.

The disease is almost completely prevented by RhoGAM, a drug developed in the 1960s by Columbia researchers John Gorman, MD, and Vincent Freda, MD, and a pharmaceutical company researcher, William Pollack, PhD. In February, Columbia researchers and physicians joined guests from around the world to celebrate RhoGAM’s 50th anniversary.

“I still marvel at how a low-tech solution could have such impact,” said Dr. Gorman, former director of the blood bank at what is now NewYork-Presbyterian/Columbia University Irving Medical Center, to the audience gathered for a panel discussion to celebrate the drug. “It’s the most cost-effective drug ever produced. There have been no fatalities in 50 years, and it saves $1 billion every year by preventing high-risk Rh pregnancies. Plus, there’s peace of mind for Rh-negative mothers. How lucky can you be?”

Rh disease can develop when a woman with Rh-negative blood is pregnant with an Rh-positive fetus. In these cases, when fetal red blood cells cross into the mother’s circulation—usually at delivery—the mother’s body begins producing antibodies that can attack and kill a fetus’s red blood cells. It takes some time to produce such antibodies, so the first Rh-positive child is typically spared. But each subsequent Rh-positive fetus increases the odds the mother will become “sensitized” to the fetus.

Once a woman is sensitized, her antibodies can cross the placenta to destroy the red blood cells of her fetus, which can lead to miscarriage, brain damage, or the newborn’s death. Roughly 15 percent of American women have Rh-negative blood.

Dr. Gorman set out to cure Rh disease with Dr. Freda, an obstetrician, and Dr. Pollack, chief research scientist at the Ortho Pharmaceuticals lab. Two physicians based in Liverpool, England, Cyril Clarke, MD, and Ronald Finn, MD, were independently pursuing the same goal. Alvin Zipursky, MD, a Toronto-based pediatrician, who was working in Winnipeg at that time, was studying the extent of the transfer of fetal red blood cells into the maternal circulation throughout pregnancy and at parturition.

By the early ’60s, when the researchers started their work, much of the scientific foundation for such a treatment already existed. It was known, for instance, that Rh disease would not occur if Rh-negative mothers did not develop the antibodies. It was also understood that injecting someone with antibodies made by other people against a given antigen prevented the recipient from producing her own antibodies against that antigen.

That suggested to Drs. Gorman and Freda that administering anti-Rh antibodies to an Rh-negative mother soon after delivery would prevent sensitization to the Rh antigen and subsequent Rh disease. Technically, the breakthrough had been possible since 1941, when Philip Levine discovered the cause of Rh disease. It just did not occur to anyone to put it all together.

“Vince Freda and Bill Pollack grasped this triple conjunction immediately,” Dr. Gorman said. “And they had the will and the resources to do something about it. They turned this idea into reality, doggedly overcoming difficulties, withstanding the immediate pushback, doubt, and skepticism of virtually the whole blood bank community.”

Perhaps the skeptics had a point: Rh immune globulin (RhIg)—the anti-Rh antibody in RhoGAM—is paradoxically the same agent that causes Rh disease and can kill babies in the womb. And the more “dangerous” the antibody, the more effectively it prevents sensitization.

“But there it was: RhIg, a fully optimized molecule, in plentiful supply from the legions of Rh mothers already Rh-sensitized,” said Dr. Gorman. “No need for clever chemists to synthesize, fine-tune, and test a novel molecule, as is the case with most new drugs.”

In the mid-1960s, Drs. Gorman and Freda obtained anti-Rh antibodies from Dr. Pollack and showed that they prevented sensitization in Rh-positive subjects, paving the way for RhoGAM’s official regulatory approval in the United States in 1968.

The benefits were immediate. The first person to receive the approved drug—Marianne Cummins—received the injection just hours after it became available. Ms. Cummins, her husband, and her physician, David Landers, MD, were also present in February to tell her story. In 1968, Ms. Cummins was 29 and pregnant with her third Rh-positive child but had not become sensitized. RhoGAM prevents sensitization—as long as it is administered within 72 hours after delivery. She had read in the newspaper about the new treatment, which was to be released on June 1. However, her due date was May 27. If she delivered on time, she would miss the chance to use the drug by one day.

After the Division of Biologics Standards (the forerunner of the FDA) approved the drug, the release date was moved up to May 29 and on that day, at Holy Name Hospital in Teaneck, N.J., Ms. Cummins became the first person to receive RhoGAM. She would go on to have another child, but this time with a newfound peace of mind.

Within a year of RhoGAM’s debut, nearly every pregnant Rh-negative woman in the United States, Canada, and most of Europe received the drug, saving the lives of millions of Rh-positive babies. For their work, Drs. Gorman, Freda, Pollack, Finn, and Clarke received the Lasker Award in 1980.

“I was very happy that Rh disease was eliminated [here], as were all my colleagues,” Dr. Zipursky said at the celebration, “but about 10 years ago, I suddenly realized that maybe Rh disease is not gone,” noting that getting it into the hands of mothers in poor countries is a remaining challenge.

Dr. Zipurksy and Vinod Bhutani, MD, a neonatologist from Stanford University, founded CURhE, the Consortium for Universal Rh Disease Elimination, to increase access to and affordability of RhIg. The consortium is joined in this endeavor by other groups that sent representatives to the February panel discussion: Funmi Banire, founder of Rhesus Solution Initiative, a Nigeria-based NGO, and Gerard Visser, MD, PhD, a Dutch obstetrician and member of the International Federation of Gynecology and Obstetrics.

“I thought the problem of Rh disease was over,” Dr. Visser said, “until CURhE showed it still exists in half the world. Three hundred thousand children dying or being handicapped every year is just too many. We know preventative measures are always preferable. It’s so easy. Why aren’t we capable of doing the easy thing?”

RhoGAM is now produced by Kedrion Biopharma, which co-sponsored the 50th anniversary event.

— Joe Neighbor