C (5:28)

I think it's a really wonderful addition and important not because it's something that we see all the time, but as you just heard from Allison, so many patients with hypermo hyperparathyroidism in pregnancy either have their disorder unrecognized or when it's recognized, don't really have the opportunity the time to for a fulsome conversation about what might be the best course for them and for their unborn baby. And so the more that we as healthcare providers know and understand, the better off our patients will be. Before diving into a discussion of individual and specific complications of primary hyperparathyroidism in pregnancy, it's important to place this conversation and this manuscript in a bit of a historical context. And that's because it's essential to recall the evolution of the clinical phenotype, a type of primary hyperpara over the last 50 years. The multichannel autoanalyzer was only introduced in the 1960s. It was invented then and it only came into common use in the 70s and early 80s. And before this time, all cases of primary hyperparathyroidism were symptomatic. That is to say, they only came to light or were diagnosed as part of the work of particular symptoms. Asymptomatic primary hyperparathyroidism was not really recognized as a clinical phenomenon until the late 70s as a question, and really confirmed as a clinical entity in the 1980s. So many of the studies, and some that are actually included in the reference list of this particular manuscript. But many of the studies that were published and that made up what we call the literature on primary hyperparathyroidism in pregnancy actually describe a different disease. It's really symptomatic rather than the asymptomatic hyperpara, with calcium levels that were significantly, in some cases markedly higher than we see today, usually. So in non pregnant people, asymptomatic hyperpara has way less symptoms, way less frequent. Kidney stones, osteitis, fibrosis cystica is a rarity, pancreatitis is almost never seen and the calcium levels are only minimally elevated. So one might expect that as we approach Any new or recent addition to the literature on hyperparine pregnancy, we might expect that we would see a very different clinical picture in these patients with milder disease. So now, after that long preamble, I will actually turn to answering the question that Allison posed to me, which is the complications themselves, what are they? Why are they there? And those complications really need to be considered in buckets, the maternal and the fetal neonatal. As Allison mentioned, there are obviously symptoms that are not specific either to hypercalcemia or to pregnancy, but they are indistinguishable from those that are seen in normal pregnancy. Nausea, vomiting, malaise, muscle aches and pains. Obviously those are difficult to attribute to one or the other. The second and more pointed are the historically very fine incidence of symptoms that are associated specifically with hyperparathyroidism, kidney stones, hyperemesis sometimes and pancreatitis. As I mentioned, those are all still seen in primary hyperparathyroidism and in pregnant persons with hyperpara, but much less commonly and frequency are related to the level of serum calcium. The third part of the maternal bucket are the postnatal complications, and that is very rare. Postpartum hypercalcemic crisis can be seen if the serum calcium was very high when the calcium that had been previously going transplacently from mom into the fetus. After the fetus is gone after birth, it stays in mom and sometimes mom will become very hypercalcemic. That very, very rare even in old fashioned asymptomatic hyperpara and certainly very rare today. The fetal and neonatal complications as Allison mentioned in the older literature there's a citation of between 10 and even 30% of spontaneous abortion, stillbirth, perinatal death and a very high incidence of neonatal tetany, up to 50% in some studies. But more recent studies suggest that in fact stillbirth and neonatal death are probably around 2%, which is about what it is in non hyperparathyroid individuals. And while neonatal tetany still occurs, the incidence is far lower, closer to 10 or 15%. The adverse postnatal outcomes, the tetany, are thought to result from suppression of the fetal and neonatal parathyroid gland. And this generally is short lived, but can be seen for several months after birth and in rare, rare, rare, rare, rare cases has been reported to be permanent. As regards the frequency and to put an exact percentage, there are very limited data on the frequency of these findings in patients with calciums under 11, but we know that they're less common and the fetal complications also both relate to the degree of hypercalcemia in mom. That's about where we are.

B (11:05)

Thank you. That was a lot of food for thought. There's also some data that suggests that surgical intervention in the second trimester would reduce miscarriages and is commonly recommended in women with significant hypercalcemia. I know that you recently just mentioned the fact that miscarriages are probably a lot less than they used to be because we're seeing more normal calcium hyperparathyroidism as opposed to hypercalcemic hyperparathyroidism. Can you just comment on why the second trimester is the preferred time to intervene? Like my patients, both were third trimester, no one wanted to touch them. Could you give us a little insight into why the second trimester is preferred?

C (11:41)

Actually, first, I just want to modify if I gave the impression that we're actually seeing normocalcemic primary hyperparathyroidism. We're not. It's actually hypercalcemic primary hyperparathyroidism. It's just less hypercalcemic and some people are normal calciumic. And I'll talk about that a little bit later. But the reason that the second trimester is the sweet spot is because there are clear studies having nothing to do with hyperpara that there are deleterious effects of anesthesia on organogenesis in the first trimester. And so never mind hyperpara. If surgery can be avoided on mom during the first trimester, that is all to the good. But there are also data that the risk not only of anesthesia, but the risks to the pregnancy itself, and therefore the risks of spontaneous abortion, decrease after the first trimester. So we know why the second trimester is better than the first. But why not wait till the third baby is more ready? And the reason for that is that the fetal parathyroid development occurs mainly in the third trimester. So if that is allowed to happen, the fetus gets a constant infusion of calcium across the placenta, which suppresses the fetal parathyroid development. This is fine as long as the fetus is in MOM and is continuing to get that constant infusion, but it can lead to postnatal hypocalcemia and seizures and even death if it's not recognized when that infusion stops all of a sudden at the time of birth. So that's why the third trimester is not so great, leaving us with one the sweet spot of the second trimester.

B (13:24)

Thank you for that clarification. One of the things that is noted by the authors is that there's a paucity of studies and data about the fetal impact and outcomes in primary hyperparathyroidism. Unfortunately, just have case series or case reports. The other unfortunate thing is that many of these studies are pretty old and they show more, much more severe forms of primary hyperparathyroidism where the calciums are like 13 and higher, as opposed to more of what we see now, which is probably more in the high 1011 range. So the overall goal of the study is that it was aimed to assess the effect of primary hyperparathyroidism on rates of pregnancy, quantified pregnancy and neonatal outcomes, and, and examine the optimal treatment and timing of treatment for primary hyperparathyroid in the pregnancy. One of the other things that they mentioned that's fairly unique about it is this is the first time they've done this large sample size here in the US previously, it's been done in Israel and Denmark. So this was the first time that you would see something like this in the US So now I will turn it over to Chase to discuss the methods.

A (14:31)

Thank you. We get a good overview of why we need to understand this. There's lots of potential implications for hypercalcemia in pregnancy and so need to figure figure out what we need to be doing in these cases. So the way the authors tackle this is they use a retrospective cohort study. We have looked at numerous retrospective cohort studies over the years in this podcast, so I'll only briefly remind everyone of how these work. The key of a cohort study is that you start by splitting your subjects into at least two groups. And in the simplest way of thinking about it, you have a group of individuals who are exposed to something and you have another group who have not been exposed to that. You can sometimes have multiple. But that's going to be it in its simplest. And then, and this is what makes it a cohort study, is that you follow those individuals over time, waiting for the development of an outcome. Now, you don't always have to be following along with them in real time. That would be a prospective cohort study. What is frequently done and was the case in this study is it's retrospective. So you are going backwards and you're going through a chart review or a database. There's many different ways that you can do this, but you have to be able to reconstruct that time sequence. You have to be able to clearly show that the exposure predated whatever outcome of interest you're looking at. And that's what the author do here. They're able to reconstruct that time sequence and then, as we'll see here shortly, compare the outcomes in one group versus another. These authors looked at women between the ages of 18 and 44 who were within the Kaiser Permanente Southern California system. Their accrual period, as they labeled it, was between January 1st of 05 all the way up through May 31st of 2020. And this will be the first area where I want to get Shoney's input is how they define primary hyperpara. And they take a relatively simple way of doing this and obviously exclude some things that we could look like this. But they say primary hyperpara is if your pth is over 65, and that's within six months of having had an elevated calcium level. And they define that as being above 10.5, and again those years that they looked at.05 up to 2020. So, Shoney, a couple of related questions. So, Juan, just what are your thoughts about that as. As definitions for. For the groups here? Also, as we're getting ahead of ourselves, but anticipating pregnancy and then a lot of physiologic changes that happen in pregnancy that affect calcium levels, what do we need to be thinking and keeping in mind with all of these different numbers that the authors have laid out for us?

C (16:52)

I would say that these are pretty strict criteria for the definition of primary hyperparathyroidism. It's important to know that pregnancy is associated with physiologic changes in measurements of calciotropic hormones and calcium itself. Especially notable is the fact that total calcium levels decrease significantly in pregnancy, requiring an elevated level because ionized calcium is not measured. And that is not a criticism. I would actually criticize Kaiser Permanente if they were in fact measuring ionized calcium in everybody because it would be a horrible waste of money. But because the ionized calcium is not measured, these criteria may have missed some individuals with the mildest level of hypercalcemia because they would look normal by the total calcium criteria. Further, their criteria would miss those who had hypercalcemia and inappropriately normal PTH levels. So those people clearly we would diagnose as having primary hyperparathyroidism if the PTH was in the upper end of the normal range and even some in the middle of the normal range and even some in the lower part of the normal range. But those individuals would not have been included in this cohort because PTH was never, frankly, elevated. But what I would say is that while their criteria may have missed some cases of primary hyperparathyroidism, I do feel confident that those that they identified actually were likely to have had the disease. So on the one hand I'm laying out some deficiencies, but on the other hand I'm feeling quite confident about the people they included. The only exception, and this is something that I'm mentioning less because I think that there's going to be a bunch of people in this cohort who fall into this category, but it is something to keep in the back of our minds as endocrinologists. The only exception is FHH and fh. Familial hypocalceuria is notoriously hard to diagnose anytime, but certainly even more difficult to diagnose in pregnancy due to pregnancy associated increases in urinary calcium excretion. And so you may not see the hypocalciuria that you expect to, but I certainly don't expect that to be something that was a confounder in more than a handful of patients.

A (19:17)

Now move on to the exclusion criteria that the authors use, and they have just a few, and that includes a GFR under 30 if a patient had had a kidney transplant, history of malignancy, or if they had been in that Kaiser system for less than six months. Importantly, as we think about how these groups were collected, the authors utilize matching. So after they found everybody with how they define primary hyperparathyroidism, they also wanted to look at a group that could be their unexp group. And so they did that by matching. And so they did a three to one matching and something I think that's really important to note. We'll look at the implications of that here shortly. But they only match based on age and so it was not based on anything else. So very limited in how they approach that. And so we'll have some potential impact on how these two groups compare to one another. The authors did go on further though, understanding that these groups were not exactly the same and they did some adjustment for potential confounders. But I think it's going to be important to note that adjustment appears, as best I can tell, to have only been done for the primary outcome. And so we don't want to be thinking the same thing about the other outcomes that were looked at. And we may actually have more interest in some of those other outcomes. You'll want to be careful to recognize that these groups may have been quite dissimilar. We will come back to that here in just a second. So moving on to those outcomes to describe those, I'm going to list them only on a high level here because Allison's going to go through them in a bit more details when we get to the results. But first of all, the, the first outcome or the primary outcome was just recurrence of pregnancy. The second outcome we're going to go to the buckets that Shoney introduced us to already. But the second outcome was everything that you could put into that category of pregnancy outcomes. And as examples, that would include the birth status, the gestational age, the mode of delivery. We'll hear more about those here in just a second. The third outcome, a group that was looked at, would be the neonatal outcomes and that would include birth weight, APGAR scores and hypocalcemia, for example. So I wanted to get Shoni's input here one more time and just give us thoughts on these outcomes. And particularly since these groups may have not been terribly similar because even with that matching, the groups weren't exactly the same because there were lots of other things besides simply age there. So any thoughts about that for Oshoni as we that we need to keep in mind as we consider comparing these

C (21:33)

two groups, I think that the outcomes are the right outcomes in general. These are the questions that they were asking in the study design to go back to things that we might have to think about. In the primary hyperpara cohort, overall there was a higher incidence of ckd, chronic kidney disease and hypertension. It's important just to flag here that hypertension is not due to primary hyperparathyroidism except in certain familial cases, and my assumption is that those would have been excluded. However, the second table which looks just that who got pregnant and who did not suggest that there was no increase in these two comorbidities in those who actually got pregnant. So one might raise the question whether CKD and hypertension, but not primary hyperparathyroidism, affected pregnancy rates. But of course there aren't enough data to comment on this. But that would be the more interesting and apropos issue given the particular groups. Certainly if there had been a difference in outcomes based on the presence of CKD or high blood pressure, then one would have had to ask whether any of these differences observed were due to the comorbidities rather than to the primary

A (22:48)

hyperparathyroidism, and we will revisit that question whenever we get to the results. A couple more comments in the method. So as far as the measurements, particularly of the calcium levels as we described with cohort studies, longitudinal assessment is important. It's what makes it a cohort study. So there were longitudinal calcium measurements and importantly, the authors noted both the highest calcium level during pregnancy and also the last calcium level that was measured during pregnancy. And finally, on the statistics, just a brief mention. The authors did a sensitivity analysis and sensitivity analyses. The reason that these are done is that in any research study authors have to make decisions. They have to decide how to define something, what to include, what to not include. And there are many situations to where you could rightly criticize the authors to say, well, you maybe made the wrong decision or maybe you should, should have made a different decision here. So a sensitivity analysis is done up front when an author recognizes that there is this potential and they want to be able to demonstrate how sensitive their analysis was to that decision that they made. So particularly what the authors plan on doing here is they want to know, well, how big of an impact is it is if we include all of the subjects who had a parathyroidectomy versus we don't include them because they. Well, a couple different reasons. One is they are likely a group that had more severe hypercalcemia to start with. And then additionally they had their hypercalcemia cured in the middle of pregnancy. And so that would potentially have a positive impact. And so the authors, recognizing that possibility, did a, an additional analysis, this sensitivity analysis, where they redid it, removing all the individuals who had a parathyroidctomy. So we'll hear about the impact of that. But, but I think a solid rationale for, for why the authors wanted to do that. Okay, so that's the methodology. We're going to now move on to the results and Allison's going to walk us through the results.

C (24:36)

Those.

B (24:37)

In terms of the results, we had a total of 386 patients who had primary hyperparathyroidism and they were given age match controls. There was 1,158 of people without primary hyperparathyroidism. If we look at our tables, they do a really nice job of highlighting what the differences were between the two groups. In Table 1, they give us the basic characteristics between the two cohorts. In terms of age, there really wasn't much different. The median age was 39 in the primary hyperparate parathyroid group and it was 38 in the non hyperparathyroid group. If we look at race and ethnicity, we see that there really wasn't much difference. And the nice thing is that the number of women they have in the study is parallel to what you would expect to find in the population of California. California is roughly about 40% Hispanic Latino. And in the study they had 42% in the primary hyperparathyroid group and 47.8 in the non primary hyperparathyroid group. So you do see very similar numbers based on the race ethnicity breakdown to what you would find in the nation of California population where we do see a slight difference in terms of being statistically significant. But I would always question is it really clinically significant? Is bmi in the group that did have primary hyperparathyroidism, the median, not the mean BMI was 29.6 with a range of 25.5 to 36.8. Those who did not have primary hyperparathyroid, the Median BMI was 30.4 with a range of 24.9 to 39.9. Now of course there's really not much of a a difference. It's like about a barely one unit difference between the two. You can argue that the 29.6 is the overweight category and then once you get to 30, it's obese. But again, there's really not much difference. So even though it's statistically significant, it really doesn't make much of a clinical difference. Where we do see something that's also different is the smoking status. There were actually more people in the primary hyperparathyroid group, interestingly enough, that were either current or former smokers in comparison to those who did not have primary hyperparathyroidism. There was no real difference between alcohol use in terms of comorbidities. As mentioned earlier by Shoni, there was a difference in hypertension as well as sickle cell. There were two more people that had sickle cell in the primary hyperparathyroid group for a total of three. Whereas there's only one in the non primary hyperparathyroid group. Again, as mentioned only by Shoni, there was slightly more CKD in those who had primary hyperparathyroid. So when we look at the actual demographics, looking in terms of the covariates and calcium levels for the pregnancy, we didn't really see too many differences except for the fact that towards the end of pregnancy, unsurprisingly those in the primary hyperparathyroid group, they had a slightly higher level of calcium. Interestingly enough, that median number was still not a range that would be life threatening. We then move on to table three in which we're talking about pregnancy outcomes. We did the big difference during delivery between the two is that there was slightly more blood loss in those who had primary hyperparathyroidism. The n here was only 29 compared to a matched non primary hyperparathyroid group. Where the N was 191. So the blood loss was only 500cc's median for the primary hyperparathyroid group. Whereas in those who did not have primary hyperparathyroid the blood loss was slightly higher at 780. Again, yes, statistically significant, but it's just really clinically significant. When we look at vaginal deliveries, we see that there was more vaginal deliveries for those who did not have primary hyperparathyroidism. There were also a lot more people who had unknown mode of delivery in the primary hyperparathyroid group overall as well. Again, is it really going to make a big difference? The ends were so small. In this particular portion of the study There was only 23 people with primary hyperparathyroid, whereas there was 168 of those who had the matched non hyperparathyroidism. So that's the results by table and I think we can discuss further as a group your thoughts on some of these statistically significant analyses and the impact on the clinical outcomes.

A (28:57)

Yeah, one thought that I had had on, on that initial one where they're just comparing those two groups initially is yeah, the, the authors described as well, we have some of these things that are cl. Calcium was expected that that's what they're looking at here. And then on top of that, Shoney already mentioned hypertension and CKD a little bit different. And then a couple of other ones, the BMI and the smoking status, that while statistically different, maybe was such a trivial difference that you would have a hard time arguing that it's clinically meaningful. It at least raises the question in my mind though, because there are so many of these things. I'm just not sure how similar these groups are particularly. It's fine with that primary outcome because you're adjusting for all these things, so you can largely account for that. I would just worry as we move into the other outcome outcomes as to where you're not adjusting for those differences. How different are these groups? And maybe it's more than just this. Maybe these handful of things that we actually identified were different. Maybe that's also telling us that these groups are, are far more dissimilar than we would like them to be. So at least raises that question in my mind.

C (29:54)

One other thing to think about is that the association of a higher C section rate in patients with primary hyperparathyroidism, which is a finding in other population studies of pregnancy and primary hyperparathyroidism, is not that surprising. And we can discuss that a bit later. But then what I consider is almost a corollary, or a potential corollary is that there's a higher blood loss during delivery in a vaginal delivery than there is in a C section. And so this is one area where it highlights the difficulty of attribution in population studies. So there are findings, but attributing the findings to the underlying category, in this case primary hyperparathyroidism, is the fact that these people with diagnosed primary hyperparathyroidism had a higher rate of C section. Could have been because people were more worried about them, they checked them more commonly. They said, oh, by the way, you chose not to have surgery, but we're going to make sure that everything is very well controlled. And so we are not going to allow you to go to 40 weeks. We'll bring you in at 39 and do a C section. One of the other, and actually arguably the largest population study, which was the Danish study that Allison alluded to earlier, where they had 1000 primary hyperpara and 3000 controls, also found higher C section rate, shorter gestation, and interestingly, they reported a higher live birth rate in the first year after diagnosis in the patients with primary hyperparathyroidism. This is a great example of just what I was saying. None of us think that primary hyperparathyroidism causes pregnancy and causes a higher live birth rate. It's just that these are individuals, individuals who are known to have primary hyperparathyroidism and therefore in all likelihood were observed more carefully. And so this highlights an example of the difficulty of attribution in people who are in a disease category.

B (31:56)

Thank you both. And then the third outcome we looked at is the neonatal outcomes in live births, as well as the calcium levels and pregnancy outcomes amongst those with primary hyperparathyroidism. So when they looked at things such as birth weight, apgar scores at 1 minute and 5 minutes, hypocalcemia in the neonate, and the requiring calcium supplementation in the first seven days of life, as well as tetany seizures, NICU admissions, nicu, length of stay, fetal anomalies, they actually found no difference between the two groups. The irony is the one baby in the whole group that had hypocalcemia was actually in the, the non primary hyperparathyroid mom group anyhow. And the two babies that required calcium supplementation for the first seven days of life, they also were in the non primary hyperparathyroid group. So there really was no difference in the neonatal outcomes. There was an end of only 23 in the primary hyperparathyroid group and of the matched controls there was 168. Now, if you look at a little bit deeper at the calcium levels in the actual women either prior, during or after pregnancy, we can see that that those who had a parathyroid surgery before pregnancy, that their calcium before pregnancy, the median was 9.1 and that their highest calcium prior to having surgery was only 11.3. During the pregnancy, the median was 9.3. So these folks did not really ever have a super high calcium based on this, because even if you look at the interquartile range of the median, it was 11.1 to 11 point. For those who had it during the pregnancy, you can see that the calcium before pregnancy was a bit higher. So it was 11.4. And their highest calcium prior to having the surgery was 11.8, which is a little bit higher than those who had their parathyroid surgery beforehand and during the pregnancy, their calcium, the median was 8.8 after they had the surgery, not before. And for those who had their surgery after pregnancy, their calculation calcium before pregnancy wasn't that bad, which is to the point of Shoney, is probably why they were missed. Median was 10.6. And then during pregnancy, even so, it still wasn't that bad. It was 10.3, which was higher than the other groups, but still not as high as it could have been. Most of these patients, whether they had the surgery or not, they were able to have a live birth. And those who had the surgery before pregnancy, there was two abortions. The ones who had during pregnancy there's one abortion and after pregnancy there's four. But keep in mind, the numbers were small. For all of these, only 22 had a surgery before pregnancy, five in the second trimester and 23 after. So it's a little hard to make big conclusions about this. But I will turn it over to Chase so we can wrap it up with a discussion and conclusion.

A (34:51)

And we will start with where the authors start as they summarize their findings. So, first of all, they say that women with primary hyperparathyroidism had similar rates of achieving pregnancy as age match controls who did not have primary hyperparathyroidism with slightly lower live birth rates and similar neonatal outcomes. And I'll comment on there that while there may be some trends there based on statistical significance would actually describe those groups as quite similar. As far as those outcomes. The authors report that the approach of women with more severe hypercalcemia having a parathyroidectomy before pregnancy or in the second trimester yielded similar pregnancy outcomes. They also point out that primary hyperparathyroidism does not appear to impact for utility. As is typical in these discussions, the authors go on to review the medical literature. And as we've talked before, a lot of this medical literature being fairly old, it does show fairly variable findings. But this report is similar to several other previous reports. There were a couple of recommendations that came from the authors. They say the same thing but stated in slightly different ways. So I want to quote the authors here and then we'll discuss that as a group. So they say first of all, parathyroidectomy before becoming pregnant should be considered the option optimal management strategy. And then the second quote from them is that we would recommend parathyroidectomy prior to pregnancy when possible. So what I want us to do is to discuss these recommendations, kind of a similar idea here as a group. And maybe I'll just be contrarian, just to help with the conversation in here, say I'm curious and maybe I would push back on that. Say the authors look at this in every different way and they can't really show any difference no matter how you approach this. And admittedly it's a small study, so it's going to be underpowered. So you couldn't be confident about any of these conflicts conclusions. But if you were going to ignore that and just look at the data here, you would say it doesn't really seem to matter what you do. So why would we be necessarily recommending that you need to have a parathyroidectomy before becoming pregnant when the outcomes are always the same? So Shona, you think a lot about these sort of things. Why don't you give us your thoughts on that? How would you wrestle with that recommendation that come from the authors?

C (36:55)

No, I would wrestle with the fact that they made this recommendation based on this paper. On the other hand, I think it's exactly correct. I don't think that the data that they have have supports this particular recommendation in a strong way. But my reason for that is that they have almost no people who had second trimester parathyroidectomy. They had five people in 15 years. To base any recommendation on five births over the course of 15 years makes no sense to me. On the other hand, if you have a person in front of you on the other side of the desk who has known primary hyperparathyroid and you ask them about their plans for pregnancy and they say that it is something that they're planning, they may not know exactly when. I always tell them that they should very strongly consider parathyroidectomy because they don't actually know what their particular situation is going to be, how high the serum calcium is going to go in pregnancy. And it can change. If they would have totally, aside from their primary hyperparathyroidism, been somebody with more vomiting instead of less, they become volume depleted, the calcium goes up, they have more and more symptoms, and then they are individuals who need to consider a surgical procedure during pregnancy. It should also be mentioned, and again, this is way beyond the scope of this particular paper, but surgery that is done apart from pregnancy can have every kind of localization technique in advance of the surgery. And therefore, one would hope and expect have a better surgical outcome than surgery done in the second trimester, even though that's the right time to choose if one needs to. No, surgery in pregnancy is always better than surgery in pregnancy. And the limitations on preoperative localization are quite severe. Ultrasound is great, but the things that we usually do considering for DCT or other modalities are not options during pregnancy. There are several times in the manuscript that it said, or it's a parathyroidectomy prior to pregnancy or during the second trimester. I can't see anybody who is given a full panoply of options with a good discussion of what the potential downsides are. I think that most people would choose something that would be both easier for them as a pregnant person and certainly safer for them, their fetus.

A (39:33)

Allison, agree with that or have a different perspective?

B (39:36)

Yeah, no, I wanted to add something else that's a little also beyond the scope of the article. But it's really important that we need to think about, and that's breastfeeding. One of the issues I had was my patient who wanted to have a parathyroidectomy after was that she wanted to breastfeed. And we know that breastfeeding can take calcium out the bone. And then you have somebody who's just gone through having primary hyperparathyroidism. So we have to think long term. So if you know that you wanna breastfeed, because we know breastfeeding is great, antibodies bonding with your baby, doing the surgery upfront would definitely help prevent some of the compromise that can happen to the bones. So that would be my other argument is that if a woman wants to have a healthy pregnancy as well as have the opportunity to breastfeed, it would be to her advantage to have the surgery beforehand. So this way we have minimal skeletal damage.

A (40:22)

And at the end of the episode we will come back to other implications on clinical practice that we might say suggest the authors here go on to discuss their limitations, and they first of all say, well, this is a retrospective study, and we've talked about that. The authors list several issues that come along with retrospective studies. Things like, this isn't randomized because it's observational. There's always a worry for coding, inaccuracies, missing data, etc. The authors also point out this is small sample size, and we've talked about that as well. They highlight the differences in hypertension and CKD between the two groups and the impact of that. And finally, they also mentioned that there's a possibility of a detection bias in women with primary hyperparathyroidism. That's very much what Shoni was getting at when she was describing how knowing that a woman has primary hyperparathyroidism could affect how you treat them, how you investigate, how you monitor, et cetera. So the authors wrap up in their conclusions. They summarize their findings here by saying that women with primary hyperparathyroidism had a slightly lower live birth rate with similar rates of pregnancy and neonatal outcome outcomes and what I would describe as an implication from them. So they say that performing parathyroidectomy before pregnancy or during the second trimester of pregnancy appears to be a safe and successful strategy. And adherence to this strategy may be most critical for patients with higher calcium levels. So, again, well, we'll finish up here in just a second with thinking about clinical care and what we might suggest as what we need to be doing, particularly based on the findings that the author's report here. But before we get to that, let's just think about the quality of this report overall. Allison, you spent a while working through this. What's your sense of the quality of this data as reported by the investigators here?

B (42:01)

I think it gives us a baseline from where we can begin. We know that obviously you'd want to have more of a prospective study to really get a better idea, but I think it gives you a solid foundation that having primary hyperparathyroidism may not compromise a woman's chance to get pregnant, and it may also not compromise her ability to have a wonderful, healthy pregnancy. Yes, there can be poor outcomes, but we know that pregnancy itself, you are at risk for having outcomes that can happen. So having primary hyperparathyroidism may increase the risk of hypercalcemia, but it may not necessarily increase the risk of fetal loss, fetal demise, tetany, and some of the extreme things that we can see with severe hypercalcemia in pregnancy.

A (42:43)

Shimoni, same question for you. Thoughts on the quality of this report?

C (42:45)

Overall, I totally agree. I think that it's very useful because as Allison mentioned, this is an American cohort and to date the only data and population studies have come from Denmark and a smaller study from Israel. So I think that it is confirmatory in as much as there's no data that suggests that achieving pregnancy is a problem, and there are ample data that suggest that achieving a good outcome from pregnancy is certainly an option. I have some trouble with their feeling that they take one implication a little farther than the data might suggest and then they don't make much of another implication from the data, which is that for patients with very mild primary hyperparathyroidism, the flip side of the severe hypercalcemia observation through a normal pregnancy is associated with excellent maternal and fetal outcomes. So they put their emphasis on a different syllable and now I'm looking at it from the glass is half full as opposed to half empty and saying that in fact, one of the other implications from their data are that people do pretty well if their calcium is on the lower side. And this adds to a small but significant amount of data that suggests that if people are pregnant with calciums below 11, and that's something that we see commonly these days, that observation through pregnancy is pretty safe for mom and the baby. It is important to put an underline on the word observation. It isn't to to say, well, you have primary hyperparathyroidism and the data says you're going to be fine and the baby's going to be fine. They have to be observed and a multidisciplinary team is warranted. So we may talk about that a little bit in the practice part.

A (44:35)

Yeah, Shoni, let's stay with you to wrap up. So give us your thoughts about does our clinical practice need to change? Does this confirm what we do right now? What other questions are out there that are maybe even outside the scope of this paper? Medical management being one example of that. So what other things do we need to be thinking about as far as moving our clinical practice forward?

C (44:54)

So I don't think that we need to change our practice per se. I think that many people still hearken back to the old literature where the worries about horrible outcomes were much more prevalent. There is a study by Dr. Norman from Tampa that was the medical main case studies that was quoted for many, many years where there was a 48% spontaneous abortion rate and that was held up as something that people should be worried about. So I do think that making sure that all of our endocrine colleagues are updated on the most appropriate guidelines at this point, since as the person who has headed the guidelines committee in the last four international consensus conferences on asymptomatic primary hyperparathyroid we address pregnancy. But it's sort of not in a particular guideline. It's just sort of tucked in in a paragraph that nobody sees, because primary hyperparathyroidism in pregnancy can clearly lead to adverse fetal and maternal outcomes if not managed appropriately. But I think that the goal would be parathyroidectomy prior to pregnancy if it's diagnosed in pregnancy, parathyroidectomy in the second trimester for a calcium well over 11. But if somebody does not have a calcium over 11, it's pretty safe to watch. As I mentioned before, a multidisciplinary approach for those babies is important. The endocrinologist has to speak to the obstetrician and to the pediatrician or the neonatologists about what the plan is. And as was mentioned, there are a whole host of medical management options, some of which were alluded to adequate hydration, stopping calcium supplementation and taking people off thiazides and lithium if possible, but also pharmacologic options about which we know nothing or very little. Cinacalcet has been used. It's a Category C calcitonin has been used Category C. None of these things are particularly desirable, but they are things about which we could all use more data and more input. The only other thing I would mention as a reminder is that the antiresorptives which are used in hypercalcemia in other scenarios, bisphosphonates and denosumab are both Category D in pregnancy and should not be used due to effects on bone development.

A (47:15)

And with that, I would like to thank Allison Myers and Shoni Silverberg for joining me for this month's edition of Endocrine Feedback Loop. I know that you all learned a great deal and hope you will join us again next month. And now you're in the loop. This has been Endocrine Feedback Loop. Endocrine Feedback Loop is brought to you by the Endocrine Society with Protection Production Oversight by Brandy Brown and Andrew Harmon. If you want to like and subscribe, you can find us on Apple, Spotify, or wherever you get your podcast. We'd love to hear your feedback on this episode of the podcast itself. Please email us@podcastron.org. Endocrine Feedback Loop is a free service of the Endocrine Society. To learn more or to become a member, visit the society's website at www.endocrine.org.