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BackTable / OBGYN / Article
Rethinking RhoGAM: New Evidence & Global Perspectives
Grace Dima • May 5, 2024 • 35 hits
In the United States, RhoGAM is used rather liberally in the care of Rh-negative pregnant patients. However, OBGYN Dr. Matt Reeves shines light on the lack of evidence these practices have in scenarios like abortions and ectopic pregnancies. Recent findings have prompted a reconsideration of guidelines, with some bodies now recommending against RhoGAM use up to 12 weeks of pregnancy. As pressure to use RhoGAM more judiciously increases amid supply threats, an examination of global administration practices highlights international variation in RhoGAM administration practices. Although change to US clinical practice is anticipated to be slow, rapid adoption can already be seen in certain areas like medical abortions via telehealth.
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
• New studies using flow cytometry indicate minimal fetal blood exposure during abortions, questioning the need for traditional RhoGAM practices in Rh-negative mothers with first-trimester vaginal bleeding. The Society of Family Planning now recommends against RhoGAM administration at less than 12 weeks gestation.
• Although RhoGAM is standard practice in the US, its global usage is diverse. For instance, Sweden opts out of using RhoGAM for first-trimester abortions, sparking discussion on the utility of tailoring RhoGAM administration protocols to align with regional contexts and specific population risk profiles.
• Obstetrics and gynecology practitioners are encouraged to reassess RhoGAM administration protocols, emphasizing the need for personalized approaches that take into account patient preferences, clinical circumstances, and resource limitations.
• As the landscape of abortion care evolves in the US, more medical abortions are conducted via telemedicine. These consultations are early adopters of the new Society of Family Planning Guidelines, typically forgoing Rh testing and RhoGAM administration.
Table of Contents
(1) Reconsidering RhoGAM Guidelines
(2) Changing RhoGAM Practice Patterns in the US & Abroad
(3) The Future of RhoGAM Use: Predictions & Perspectives
Reconsidering RhoGAM Guidelines
The limited supply and high cost of RhoGAM have prompted inquiries into its widespread use, particularly in contexts such as abortions and ectopic pregnancies, where comprehensive evidence is lacking. Recent data using flow cytometry indicates minimal fetal red blood cell exposure during first-trimester abortion procedures. This discovery has led to a reassessment of guidelines, with organizations such as the Society of Family Planning now advising against the use of RhoGAM up to 12 weeks of pregnancy.
[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.
[Dr. Amy Park]
Yes, because the full dose at 28 and term is like 300 mics, and then microgram is like, I can't even remember, it's like a hundred or something or 75 mics.
[Dr. Matt Reeves]
50.
[Dr. Amy Park]
50 mics.
[Dr. Matt Reeves]
I'm pretty sure. It's one fifth.
[Dr. Amy Park]
Then it's like total guesswork, probably. There's all sorts of questions about-- I know a couple, you know Hilary Gammill. I remember she was doing some work on like chimeric cells circulating throughout the maternal circulation and then how we were using the KB, which is a terrible task, to try and quantify fetal RBCs and the maternal bloodstream, but I don't even know, it sounds like the technology for that has really improved lately.
[Dr. Matt Reeves]
Yes. Using flow cytometry, we're able to get much better estimates of how many fetal red blood cells are actually in maternal circulation. That's where some of the newer data comes in that how many fetal red blood cells were introduced by abortion procedures. It turns out basically none. For most of the women, the difference between before and after was zero and the amount of circulating fetal.
[Dr. Amy Park]
That was for first trimester or second trimester, or how far along were we talking?
[Dr. Matt Reeves]
With the flow cytometry, there were two studies in the first trimester and neither showed any increase in fetal red blood cell exposure after the abortion.
[Dr. Amy Park]
Then our practice has always been Rh-negative moms, any kind of vaginal bleeding, first trimester abortion, any kind of vaginal bleeding at all, an Rh-negative mom, we'd be giving RhoGAM. How is this data going to change that kind of practice? We only have first trimester data, but where are we going with the guidelines, and then where do our future thinking?
[Dr. Matt Reeves]
Just to clarify, there was one second trimester study and they used KB testing. Without going into all the methods of the KB test, it does pick up some maternal cells, so it's not perfect, but they did a study using that and found no significant difference before and after surgical abortion, so it's also likely that even in second trimester abortion, the amount of exposure is pretty small. No one's ready to give up RhoGAM for second trimester yet, but for first trimester, the data is compelling enough that the Society of Family Planning has recommended that RhoGAM isn't needed through 12 weeks.
[Dr. Amy Park]
Yes, I think the ACOG is probably working on something. I'm not on the OB side, but I would absolutely think that that is coming down the pike. I saw the JAMA article and our former colleague and friend, Corrie, was instrumental in this research, Corrie Schreiber, who's at Penn.
[Dr. Matt Reeves]
Yes, it was her fellow, Sarah Horvath, who led the research. Yes, it's good research and it's very compelling.
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Changing RhoGAM Practice Patterns in the US & Abroad
Following the Dobbs decision, which has altered the abortion landscape in America, there has been a notable increase in patients opting for medical abortions and turning to telehealth services. This emerging trend prompts a consideration of international RhoGAM practices. In regions where RhoGAM availability and Rh testing accessibility are comparatively lower, insights from these countries could potentially enhance our practices in the US. However, it's crucial to acknowledge the limitations of such comparisons, particularly concerning Rh-negativity and abortion rates. For instance, while Sweden refrains from administering RhoGAM in first-trimester abortions, its exceptionally low fertility and abortion rates pose challenges in extrapolating data to the US context. Ethiopia also abstains from RhoGAM administration, however, there is limited data on Rh alloimmunization rates in the country.
The United States has seen significant changes not only in its abortion landscape but also in fertility rates over the past century. These shifts may have implications for the administration of RhoGAM. Typically, Rh alloimmunization does not reach severe levels until a patient's third full-term pregnancy, even without prior RhoGAM administration. However, this occurrence is becoming increasingly rare, particularly with the decline in fertility rates. This leads to a discussion about the role OBGYNs play in navigating the balance between individual patient care and public health concerns amidst shifting trends in abortion and fertility rates coupled with the restricted supply of RhoGAM.
[Dr. Amy Park]
Then how does the US compare to the other countries in terms of practice patterns and what are they seeing in terms of sequelae?
[Dr. Matt Reeves]
Yes, WHO is already-- and they have a slightly different audience because they're international where often RhoGAM isn't available, but a lot of this becomes very relevant in the US with the changes since the Dobbs decision last year where a lot of women are using mifepristone and misoprostol. One of these studies was medical abortion. Being able to say that you can do mifepristone and misoprostol without needing RhoGAM just makes it a lot easier for folks who may not have access to testing and RhoGAM.
[Dr. Amy Park]
Didn't you tell me that most of the world, nobody else gives RhoGAM?
[Dr. Matt Reeves]
Not the way we do, that's for sure. Yes.
[Dr. Amy Park]
Are they giving it at 28 weeks and at term too?
[Dr. Matt Reeves]
In some places. There are parts of the world where Rh-negativity is fairly common. I have always been taught it was most common in the Basque and Celtic population, which is true if you have a Western European-centric point of view, but it's also even more common in Saudi Arabia and parts of the Horn of Africa around Ethiopia and Somalia, where it can be up to 20% to 30% of the population, and I don't know the data on what their Rh alloimmunization rates are. You also have to keep in mind where we are in terms of average numbers of children per family, per person.
Really the problems with Rh alloimmunization typically don't become severe until the third pregnancy. That's without any RhoGAM at all, and third full-term pregnancy, that's just not that common anymore. Sure, people have a third pregnancy, but not many are having many more than that. Most are having one or two. The demographics of fertility have changed a lot. 100 years ago or even 60 years ago, larger families were much more common, so it's much more important to use RhoGAM to prevent applications and additional pregnancy.
[Dr. Amy Park]
That's such a good point. That did pop into my mind. The average fertility, the median rate in a lot of countries is less than what needs to be, I think it's 2.4 or something in order to replenish the population, but it's super skewed. East Asia, it's like less than two, the US is hovering around two, but in Africa and India and a lot of other places, it's still quite high. I don't know the numbers.
[Dr. Matt Reeves]
Yes. For the US, when you combine the Venn diagram of fewer pregnancies per person and we're already giving a lot of RhoGAM that it becomes less important to give RhoGAM in pregnancies that really are very low risk. That the likelihood of Rh alloimmunization is extremely low. It does happen and it is seen in some. I saw one case in residency and it was a patient who had some sort of trauma, I think a gunshot probably. They were out of Rh-negative blood, so she was going to apparently might've died. They gave her blood, Rh-positive blood in the hope that she was Rh-positive and she wasn't, so she got a full unit of Rh-positive blood and she was sensitized and had alloimmunization with her subsequent pregnancy. Barring that, incidents like that, it's almost unheard of.
[Dr. Amy Park]
Yes, I know. I don't think I saw one case in residency. Yes, that is super interesting. Then you were telling me in Sweden or somewhere in Scandinavia, it's also super rare and they don't routinely give it, right?
[Dr. Matt Reeves]
Yes. That's where the demographics issue comes in. In Sweden, they don't use RhoGAM for first trimester abortion and they have great research databases, so they do these great population level research databases. Several of us went to some researchers and said, "Could we look at this?" Could we look at Rh alloimmunization and who has it and whether they've had medical abortions and does it cause it?
They went and looked at it and basically they found that there are very few abortions because they have great access to contraception, few relative to the US, and their total fertility is so low that there are very few pregnancies after a medical abortion didn't get RhoGAM, too few for them to look at. That's a country of five million people, so there aren't a lot of Rh-negative people who had a medical abortion who then go on to have a live birth. When you combine all those aspects, you get down to very few patients, and I said, "Not enough to look at," because there aren't many pregnancies, aren't many kids being born in that group or any group.
[Dr. Amy Park]
That's super interesting. It sounds like we need to go to Saudi Arabia and the horn of Africa [laughs] and ask what the–
[Dr. Matt Reeves]
They don't use it at all in Ethiopia. I don't know what their Rh alloimmunization rates are. I was in Ethiopia early this year and we talked about it. They said, "No." They said, "Yes, we do see it every now and then," but they couldn't really say whether it was related to the abortions or just lack of RhoGAM generally, so it's not clear, and maybe they'll be able to do some research on it, but we don't have any information there.
[Dr. Amy Park]
That just begs the question, what is our responsibility as OBGYNs in terms of safeguarding individuals versus like a more public health lens on isoimmunization versus the RhoGAM supply and production issues, because I know when we talk about-- I don't know, I'm just going to give an example that came up, like how we screen for endometriosis or whatever, and our Canadian colleagues are like, "Oh, well, we--" They just have a very different viewpoint on it. There are just not enough advanced MIG surgeons to deal with this whole issue, so it's super referred and they just use everything as these very strict public health guidelines. The US, there's guidelines, but it's a little bit more individualized approach, and it seems like RhoGAM is definitely a public health kind of-
The Future of RhoGAM Use: Predictions & Perspectives
Historically, there has been a low threshold for RhoGAM administration in clinical practice. Questions arise regarding the appropriateness of universally administering RhoGAM, particularly in cases where patients do not plan future pregnancies. Looking ahead, there may be resistance to altering clinical practices surrounding RhoGAM. However, there is evidence of swift adoption in certain areas, such as medical abortions via telemedicine, where routine Rh testing is not conducted. Nevertheless, widespread adoption of changes may be slow and influenced by factors like supply chain dynamics as RhoGAM becomes increasingly scarce.
[Dr. Amy Park]
What is your take? What are your feelings on this? How do you see this story evolving?
[Dr. Matt Reeves]
I think for a long time, it was basically with RhoGAM, the case of the more, the better, but there didn't seem to be any harm to using lots of it, so patient comes in with a little spotting and they're Rh-negative, "Give them RhoGAM." Anything you do that might cause any fetal blood into the maternal circulation, "Give them RhoGAM," and without really evidence to verify that there's actually a need for RhoGAM.
As the supply is decreasing, and the potential benefits are less, because if you only have three pregnancies in your lifetime, and how much you're getting, say the first one you got the full dose of RhoGAM as term, and the second one's a miscarriage at five weeks and you have a uterine aspiration, what's the benefit to you as a patient for that? Presumably you want a third pregnancy. Even more than that, RhoGAM has been routinely administered to women who are at the end of their childbearing who have an abortion. They have absolutely no desire to have a future pregnancy.
Say they're 40, 42 years old, have an unintended pregnancy, their other kids are teenagers. Most abortion providers in the country would almost force that patient to have RhoGAM. It really wasn't even a discussion, and there was no shared decision-making about, "Is it worth it for me to give RhoGAM?" When you throw in there how it's made, I think a lot of patients might think twice about it. It's not an entirely benign substance. It is pooled human product from men, as you pointed out, who maybe aren't in the best circumstances.
[Dr. Amy Park]
I'm sure there's a screen.
[Dr. Matt Reeves]
I don't know how it is now. Back when it was it all the –
[Dr. Amy Park]
I'm sure there's a screen, but we've come a long way from our prison roots. [laughs] If RhoGAM–
[Dr. Matt Reeves]
I don't know who's doing it now, but people are going to take blood products from 100 prisoners at Sing Sing and inject it into you. How do you feel about that?
[Dr. Amy Park]
Oh my God.
[Dr. Matt Reeves]
Regardless of where they're from, they take a pooled product from 100 men and inject it, when you have no desire to have another pregnancy, you're not concerned about future alloimmunization. In the bigger picture, there's a shortage really internationally of this product. I think that shared decision-making and that viewpoint on using what's becoming a scarcer resource has changed how we're using RhoGAM.
[Dr. Amy Park]
Yes, it is interesting, because it never even occurred to me about stewardship of this resource. It's just like giving blood products. Just generally speaking, I remember people just being like, "Let's just give two units," and then we were going by these numbers, like he will go into 10 cardiac patient, whatever. Then I just saw this whole series in JAMA about how restrictive transfusion is better, and they use a cutoff of seven grams per deciliter.
[Dr. Matt Reeves]
That came out when we were in medical school, that study of the 7 versus 10.
[Dr. Amy Park]
Oh really? I didn't even realize that.
[Dr. Matt Reeves]
Yes. It was a randomized trial in the late '90s, early 2000s. Yes. It took a while to get into practice.
[Dr. Amy Park]
Over 20 years later. I went to medical school-
[Dr. Matt Reeves]
Yes, that's typical.
[Dr. Amy Park]
-in 1998 to 2002. Anyway, there's chronic blood shortages. The screening is intensive and I don't know, I didn't even think about it, that moiety must be so big that it just has to be pooled, like you said. I don't know how many people they require, but I've never even seen volunteers for this. Do they use it through the blood bank or how does that work?
[Dr. Matt Reeves]
I really don't know the details of how it's made. I don't know how they recruit people. I guess maybe if you're Rh-negative, you get targeting advertising on Instagram.
[laughter]
[Dr. Amy Park]
Yes. No, that's true. That's true. Then where do you think that in terms of, do you think that with maternal trauma or these other things, we always used to get these patients like car accident, we send a KB, whatever. Is it feasible to do flow cytometry to quantitate these things and have a little bit more precision about titrating RhoGAM dose?
[Dr. Matt Reeves]
Not anytime soon. I know for the studies that Sarah Horvath did with Corrie Schreiber, that they had to set up their own lab protocol. They weren't doing it through the routine hematology lab. They had to set up a whole special area to do their flow cytometry. It was not coming to a lab near you.
[Dr. Amy Park]
Then what do you think is the resistance or the uptake going to be? Because I think there's a lot of–
[Dr. Matt Reeves]
Oh, yes. I think it'll take a long time. In some cases, it's going there quickly. The one area is medical abortion by telemedicine. Using mifepristone and misoprostol via telemedicine, which has just dramatically increased over COVID and with these recent abortion bans in many states. Basically, most of those telemedicine programs have already implemented the SFP guidelines. They aren't doing Rh testing, so they don't even know, so there's not a lot of RhoGAM being used in those. The number of abortions being performed by telemedicine has increased dramatically. In that way, I think the impact has already begun. When it gets to the community level, maybe like the study of the transfusing at 7 versus 10 for ICU patients, that may take 20 years. Hopefully not, but it may take a while before that's really implemented.
[Dr. Amy Park]
You know what's interesting is I think sometimes the supply chain will just force our hands because-
[Dr. Matt Reeves]
Maybe.
[Dr. Amy Park]
-COVID basically made us all adopt telemedicine, and then supply chain issues made us be more green. We couldn't get certain things.
Podcast Contributors
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
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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