The Surprising Origins of RhoGAM & Its Role in Pregnancy

[Dr. Matt Reeves]
Imagine most know about Rh alloimmunization in women. It's when an Rh-negative woman has an Rh-positive fetus, and during the birth process, she is exposed to some of the blood from the fetus and will develop antibodies. In the course of that, those antibodies stay. In the next pregnancy, some of those antibodies, because the antibodies from the mom cross the placenta actively, they will enter the fetus and attack the fetus's Rh-positive red blood cells in the next pregnancy.

Generally, in the second pregnancy, it's not a big deal, but with enough pregnancies and with enough blood exposure, so the amount of blood exposure varies in each pregnancy, so the sensitization can vary, but eventually an Rh-negative woman who has enough Rh-positive babies will typically become sensitized. The result when she has enough sensitization is that her antibodies are essentially attacking the fetus's red blood cells, and those cells get cleared and the fetus can develop anemia, profound anemia, and even die.

RhoGAM was developed to essentially help through a passive immunization sort of way clear the red blood cells from the patient's bloodstream so that she isn't exposed to those Rh-positive red blood cells. This is very effective, and it works great. The thing they discovered, which was a bit controversial apparently at the time, was that traditionally you give two doses, one at 28 weeks and then one right after delivery. When they started with the right after delivery thing, everyone thought that would do it. It turns out it didn't, and they had to add this dose at 28 weeks, which apparently at the time was very controversial.

This would have been in the '50s and '60s, because those antibodies, the ones that are injected, will cross the placenta as well. It's not enough to do any harm to the fetus, but it was still controversial at the time. Giving that 28-week dose is what made it not quite 100%, but very close to 100% effective. We've been doing that. We've been doing a dose at 28 weeks and a dose at 40 weeks ever since. The thing that was never really studied in any systematic way was, this is great for continuing pregnancies, but what about miscarriages? What about abortion? What about ectopic? Basically, we just went crazy giving RhoGAM to everybody for everything when there really wasn't any evidence except for those doses.

[Dr. Matt Reeves]
A lot of interesting things. I went into this meeting not really knowing anything in detail about RhoGAM, but what [the pathologist] described was that when they were developing it, they discovered that you couldn't just take serum from one man. Basically, they sensitized men by injecting them with Rh-positive blood, Rh-negative men injecting them with Rh-positive blood and they get sensitized and they could collect the antibodies from these men and then look at their neutralizing abilities against Rh-positive red blood cells.

Basically, what they found was that one-man serum wouldn't work, that you had to pool the serum of multiple men. The idea was that you basically needed to cover the Rh antigen so that all the potential epitopes on it were blocked. You couldn't just have it blocked behind one spot on the RhoGAM, you had to basically cover the thing with antibodies so that it prevented the exposed person from getting any exposure to the Rh protein, Rh antigen, and so that they had to pool it.

Because of that reason, you can't make it in a hybridoma model where you have a cell line that secretes one antibody because you need lots and lots and lots of antibody types. You can't have one antibody, you can't have two, you have to have, they didn't know exactly how many, but enough to really cover the Rh antigen. Basically, to make it, you have to take the serum from many men and then condense it down into units.

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[Dr. Amy Park]
Can we go back to what you're saying about RhoGAM development? Because what I could tell was it was developed by Columbia University researchers, it sounds like, and there were pathologists and I'm sure some heme people involved. Then it sounds like prisoners from Sing Sing were the initial Rh-sensitized individuals. Can you tell me more about that?

[Dr. Matt Reeves]
I wish I could. I can't tell you a lot more. I imagine they buried that history. I imagine they were "volunteers." I'm not sure how that happened or transpired.

[Dr. Amy Park]
They would not pass the CITI Program training?

[Dr. Matt Reeves]
Yes. The research ethics training had not been developed. Yes. Most of the initial volunteers for donating the serum were Rh-negative prisoners who were sensitized and then their blood collected.

[Dr. Amy Park]
Then do you happen to know about like, how did they scale this up? I read some article a couple of years ago that this one man who's like in his 70s was the main supplier of all the RhoGAM. Is that true?

[Dr. Matt Reeves]
I don't know a whole lot about the supply line for RhoGAM. I do know that it is limited and becoming more limited, not surprisingly, this isn't a popular line of work. There's more and more people, there are more and more people who need it and not an increasing supply. This raised the issue of do we really need to use it for all these things, the miscarriages, the ectopics?

[Dr. Amy Park]
What was the impetus for this invitation for you and these other 11 at the meeting?

[Dr. Matt Reeves]
It was really about abortion, and do we need to be giving it for every six-week abortion? Because it is becoming more expensive and more limited. Is there even any evidence that we need it? Turns out there really wasn't much, almost none.