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RhoGAM & Its Role in Pregnancy & Miscarriage

Author Grace Dima covers RhoGAM & Its Role in Pregnancy & Miscarriage on BackTable OBGYN

Grace Dima • Apr 26, 2024 • 164 hits

Rh alloimmunization in Rh-negative women carrying Rh-positive fetuses poses pregnancy risks due to harmful antibodies. RhoGAM effectively prevents sensitization but faces controversies regarding its origins and administration practices. Dr. Matt Reeves and Dr. Amy Park explore the surprising reason for RhoGAM's 72-hour rule, its development from pooled serum, and concerns about supply and widespread use, especially in the case of miscarriage, ectopic pregnancy, or abortions.

This article features excerpts from the BackTable OBGYN Podcast. We’ve provided the highlight reel in this article, but you can listen to the full podcast below.

The BackTable OBGYN Brief

• Rh alloimmunization presents risks in Rh-negative women carrying Rh-positive fetuses, leading to harmful antibody development that can negatively impact future pregnancies.

• RhoGAM is administered at 28 weeks and within 72 hours post-delivery to prevent sensitization in Rh-negative women carrying Rh-positive fetuses, clearing Rh-positive red blood cells and safeguarding future pregnancies. However, the 72-hour rule lacks comprehensive clinical evidence.

• RhoGAM's development involved pooling serum from multiple men, initially sourced from Rh-negative prisoners. The current supply chain is unclear, highlighting supply limitations and concerns about RhoGAM’s broad application in scenarios without comprehensive evidence.

• Despite its effectiveness, the widespread use of RhoGAM - especially in cases like abortion and ectopic pregnancies - lacks systematic study and may warrant reassessment.

RhoGAM & Its Role in Pregnancy & Misscarriage

Table of Contents

(1) Rh Alloimmunization & RhoGAM's Role in Pregnancy

(2) RhoGAM History & Development

(3) RhoGAM Origins & Limited Supply

Rh Alloimmunization & RhoGAM's Role in Pregnancy

Rh alloimmunization occurs when an Rh-negative woman carries an Rh-positive fetus, leading to the development of antibodies that can harm subsequent pregnancies. RhoGAM, developed as a solution in the 1950s and 1960s, works effectively by clearing Rh-positive red blood cells from the mother's bloodstream. Though initially controversial, administering RhoGAM at 28 weeks alongside the traditional post-delivery dose significantly enhances its effectiveness, yet Dr. Reeves points out that its use in cases like miscarriages and abortions lacks systematic study.

[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.

Listen to the Full Podcast

RhoGAM’s Role in Pregnancy: Facts & Controversies with Dr. Matt Reeves on the BackTable OBGYN Podcast)
Ep 45 RhoGAM’s Role in Pregnancy: Facts & Controversies with Dr. Matt Reeves
00:00 / 01:04

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RhoGAM History & Development

While it's customary to administer RhoGAM within 72 hours of delivery, this practice lacks empirical basis. Dr. Reeves reveals that the 72-hour rule stemmed from the work schedule of pathologists involved in RhoGAM's development, who did not work on weekends. Thus, this timeframe persists as a procedural artifact rather than evidence-based medicine.

[Dr. Matt Reeves]
They invited about 12 of us to discuss the issues around Rh-negativity in pregnancy, preventing alloimmunization, and what RhoGAM is. One of the post-docs, a pathologist who was around when they were developing RhoGAM was there and told us the whole story of how it developed, including where the 72 hours came from. Which of course is purely practical because they were pathologists. They did not work on the weekends, so if someone needed RhoGAM, they needed a window long enough so they could wait. That's where 72 hours came from.

[Dr. Amy Park]
Wait, what do you mean 72 hours? What does 72 hours have to do with anything?

[Dr. Matt Reeves]
Oh, you have to give RhoGAM within 72 hours of delivery.

[Dr. Amy Park]
Oh, I didn't realize that. Oh, okay.

[Dr. Matt Reeves]
Yes, the 72 hours was because they didn't want to come in on the weekend.

[Dr. Amy Park]
Tell me this story because I tried looking up a PubMed search on RhoGAM and there's a really old obstetrics and gynecology article from 1991 that is not available. If you read the abstract, it's super breathless in terms of the description.

RhoGAM Origins & Limited Supply

The development of RhoGAM involved pooling serum from multiple men to ensure adequate coverage of the Rh antigen, as individual serum sources were insufficient. Initially, Rh-negative prisoners served as donors for serum collection. However, details regarding production scaling and the primary supplier remain unclear, raising concerns about the limited supply and broad application of RhoGAM, including its use in miscarriages, ectopic pregnancies, and abortions.

[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.



[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.

Podcast Contributors

Dr. Matt Reeves discusses RhoGAM’s Role in Pregnancy: Facts & Controversies on the BackTable 45 Podcast

Dr. Matt Reeves

Dr. Matt Reeves is an obstetrician-gynecologist and the executive director of DuPont Clinic in the Washington DC area.

Dr. Amy Park discusses RhoGAM’s Role in Pregnancy: Facts & Controversies on the BackTable 45 Podcast

Dr. Amy Park

Dr. Amy Park is the Section Head of Female Pelvic Medicine & Reconstructive Surgery at the Cleveland Clinic, and a co-host of the BackTable OBGYN Podcast.

Cite This Podcast

BackTable, LLC (Producer). (2024, January 23). Ep. 45 – RhoGAM’s Role in Pregnancy: Facts & Controversies [Audio podcast]. Retrieved from https://www.backtable.com

Disclaimer: The Materials available on BackTable.com are for informational and educational purposes only and are not a substitute for the professional judgment of a healthcare professional in diagnosing and treating patients. The opinions expressed by participants of the BackTable Podcast belong solely to the participants, and do not necessarily reflect the views of BackTable.

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