Journal Review in Endocrine Surgery: Thyroid and Parathyroid Disorders in Pregnancy

</span> Welcome to another endocrine surgery podcast. I'm Bart Miller from The Ohio State University. I'll be your moderator today. I'll be joined today by the rest of our endocrine surgeons here at Ohio State, Dr. John Fay, clinical professor of surgery, Dr. Priyaditya, assistant professor of surgery, and also joining us is Dr.</p> <p>Vanila Padmanabhan, one of our current complex general surgery oncology fellows. Pregnancy is a state of complex physiologic changes. Additional endocrine surgical disorders are discovered during pregnancy and can present a risk to Maternal and fetal harm and spontaneous pregnancy loss. The stakes are higher when assessing and treating these endocrine disorders during pregnancy given multiple factors to consider and can be confusing or lead to more uncertainty and stressful decision making for surgeons and other members of the treating medical team.</p> <p>It takes good multidisciplinary communication and nuanced consideration to manage endocrine disease in the preconception, pregnancy, and postpartum periods. And this should be an interesting and engaging analysis of available literature regarding common endocrine disorders. In <span style="color:#808080">

</span> the first part, we'll consider evaluation and management of thyroid nodules, hyperthyroidism, thyroid cancer, and primary hyperparathyroidism.</p> <p>In the second part of this podcast series, we'll tackle pheochromocytoma, adrenocortical cancer, and the rare but mechanistically interesting adrenally mediated Cushing syndrome during pregnancy. We're looking forward to a robust discussion. Welcome everyone. Thanks for having us. So, Vanilla to set the stage, can you highlight the physiologic changes during pregnancy that impact thyroid function outlined in the 2017 ATA guidelines?</p> <p>We'll have a link to these excellent guidelines for the care of the pregnant patient on the podcast page. These are also available and free on the American Thyroid Association website. Why don't you give us a quick overview of what the guidelines cover in general, and then we'll briefly review the major physiologic changes surgeons should try to take away from this podcast.</p> <p>Yeah, sure. So, during pregnancy, the thyroid gland normally increases <span style="color:#808080">

</span> in size about 10 to 40 percent. And so, the accurate assessment of thyroid function differs, not unexpectedly, from the non pregnant patients. So, interestingly, beta HCG has the same structure as TSH, and estrogen stimulates thyroid binding globulin, and so the net effect is an increase in T4 and T3 levels.</p> <p>Now in the first trimester, thyroid hormone levels actually increase, this is an expected physiologic change, and so throughout the pregnancy, trimester specific assays should be applied, and iodine status for the patient needs to be considered. Now it's not really uncommon to see an increased incidence of thyroid autoantibodies develop And this is seen both as the development of Hashimoto's thyroiditis and Graves disease, which increases in frequency during pregnancy.</p> <p>Just to confound these diagnoses, patients may also have gestational transient thyrotoxicosis. And when patients do develop true or abnormal thyrotoxicosis, this can have really bad effects on the pregnancy, including pregnancy loss. <span style="color:#808080">

</span> It can cause gestational hypertension, prematurity, low birth weight intrauterine growth retardation and thyroid storm in both the mother and the fetus.</p> <p>Additionally, several severe and prolonged maternal hyperthyroidism can occasionally lead to fetal seizures and neurobehavioral disorders in the child, as well as poor fetal thyroid development. And so there's many things to consider in the occurrence of hyperthyroidism in pregnant patients. Now, there are fetal endocrine abnormalities that can develop Both on their own and as a result of maternal endocrine disorders.</p> <p>So we should be aware of that, but we don't really have time to get into that today. For thyroid issues, ultrasound can identify goiters that may compress the airway and become an issue immediately after birth. So any comments, John or Priya? You know, we all see patients who are pregnant and takes, you know, a little bit of extra thinking and when we're thinking about either an operation or does somebody need an operation or <span style="color:#808080">

</span> not.</p> <p>You know, anything you remember in particular about maternal fetal physiology when evaluating thyroid disorders? Well, one thing I always counsel my patients about before they get pregnant, when we're talking about lifelong thyroid hormone replacement, if they're about thyroidectomy, is that it does change during pregnancy.</p> <p>So, I try to stress to them that during pregnancy, they need to be followed more carefully by either their endocrinologist or OBGYN. I think I like to think about it in an overview fashion. So the three things I like to think about for pregnant patients are their physiology and how their physiology is going to be different from the from the non pregnant patient.</p> <p>And then I like to think about the risk factors for that pregnant patient for surgery versus non surgery. And then the risk factors for the non surgery. The fetus for surgery versus non surgery and so that's kind of how I go about the decision making in terms of the pregnant <span style="color:#808080">

</span> patient.</p> <p>Alright, Benalla why don't you move on to telling us about the management of patients with Graves thyrotoxicosis during pregnancy? Can you review the three general options and then how, what we offer may be different in the pregnant patient? So generally speaking, because of the growing fetus, there are different considerations in the pregnant patient.</p> <p>When we talk about anti antithyroid drugs, for example, methimazole, that is specifically contraindicate due to fetal toxicity, and while appropriate ursil crosses the placenta in the smallest post possible dose, it is an option in pregnancy for those patients with allergies and contraindications or non-compliance, and those patients in which medical management becomes complicated because we can't achieve a youth thyroid state, it's recommended to engage an endocrinologist or a high risk.</p> <p>Maternal fetal medicine specialist in terms of anti-hypertensive such as beta blockers. These are a little bit understudied, but propanolol is one option that is safe to use in pregnancy <span style="color:#808080">

</span> naturally because of the radioactive nature of RAI. This is not indicated in the pregnant patient. So we hear a lot about or worry a lot about preterm labor and fetal demise in those operated on.</p> <p>During pregnancy in the three trimesters what are the rates that, that this occurs and what's the rate of preterm labor, fetal demise if definitive management is not achieved in pregnant patients with hyperthyroidism or poorly controlled fluctuating thyroiditis? Yeah, so I think this is a really important question, particularly a prominent concern of the pregnant patient that we see in counsel in the office, and the rates are actually quite variable.</p> <p>They do, they are mentioned in the ATA guidelines, and they range somewhere between 5 15%, and so there is a substantial risk of preterm labor, labor and fetal demise for unmanaged or poorly managed hyperthyroidism. What about this scenario? How would you all handle this? I just saw this patient in clinic recently.</p> <p>She's 31 years old. She has ongoing <span style="color:#808080">

</span> flares of thyroiditis, causing hyperthyroidism and then down to euthyroidism, a little bit of hypothyroidism, back up. Kind of the usual thyroiditis story. When she's hyperthyroid, she's on PTU. Her hormone levels are controlled. Do you keep her on medication? No. Or do you take her thyroid out?</p> <p>You know, she's got a mildly enlarged thyroid gland, but nothing causing any issues. Right now, you know, well controlled. But who knows if she has another flare or not, or her thyroid just kind of, you know, fizzles out. Slightly firm, but it's not painful. She has no dysphagia or esophageal compression or airway issues.</p> <p>So, how would you counsel her? Well, let me start with I'll pick on you first, John. What do you think? So, you know, as we just heard you know, Graves disease or even Hashimoto's can be very challenging to manage during pregnancy. And I kind of think of pregnancy as somewhat of a partially immunosuppressed state.</p> <p>And so frequently those diseases can get a <span style="color:#808080">

</span> lot worse. Sometimes, surprisingly, they can get better. So. You know, I think anybody with certainly significant hyperthyroidism the, one of the first things I always stress is try not to get pregnant while you're hyperthyroid. So I, you know, I do think surgery is a reasonable option in someone who's certainly planning to get pregnant in the very near future.</p> <p>It, you know, complicates the pregnancy much less and potentially helps them get pregnant if they're, if that's going to be a challenge. We know hyperthyroidism or hypo can cause some infertility issues. So, I mean, obviously every patient's different and depends on if they're actively trying to, you know, have kids or not.</p> <p>But but all those are important factors to consider. Priya, what do you think? I completely agree. I think it's important especially in somebody that's having flares. It's going to be more challenging potentially to control those flares during pregnancy. And that could, because the flares might be poorly controlled and you might <span style="color:#808080">

</span> have highs and lows, that could put the patient at higher risk for fetal demise.</p> <p>So, I would counsel the patient to have treatment for the hyperthyroidism before considering getting pregnant. And obviously the other definitive treatment being radioactive iodine can be problematic because typically we recommend not getting pregnant for six months after they have that treatment.</p> <p>So, and if they already have young kids at home, that can pose an extra problem with that. Yeah, I think another interesting point may be that the patients that we see in clinic, We already have you know, that, that decision has already been made to send those patients to us. I know that obviously we're not operating on every patient who's hyperthyroid before they get pregnant.</p> <p>There are thousands of women who are out there who are hyperthyroid and on medication and the endocrinologist certainly manage these patients. But I think what we brought up are some, you know, interesting points to think about. You know, if they do have a flare you know, we see <span style="color:#808080">

</span> patients When they have significant issues, right?</p> <p>So we're probably biased towards one direction potentially to try and ward off some of these difficult situations that we see. So, but there are definitely lots of, you know, options and you need to think carefully about, about everything in these patients. All right, let's move on. The evaluation of thyroid nodules is essentially the same in the pregnant patient.</p> <p>Ultrasound, labs, bi needle aspiration if warranted. When we start talking about discussing indeterminate nodules and thyroid cancer. So John, in your practice, how do you manage a newly diagnosed indeterminate nodule and then a known thyroid cancer during pregnancy? Yeah, so, so that's a great question.</p> <p>We know, you know, obviously we've come a long way in our molecular diagnosis of indeterminate nodules, but to my knowledge, that is. That data hasn't been as validated in the pregnant population, so I do have a little bit more <span style="color:#808080">

</span> concern using that. But in general for patients with, you know, known thyroid cancer I try to recommend, you know, watching it through most of their pregnancy depending on how big it is and how fast it's growing.</p> <p>So, I will frequently get, you know We don't have them come back frequently for ultrasounds to monitor any change. Obviously, you know, we want to operate in the second trimester is kind of the best time to do it. You know, the data for waiting is fine. We know that most thyroid cancers progress slowly.</p> <p>It's not going to change the overall outcome or treatment or survival. And I think the Pandemic has added to that data as well because most of endocrine surgery was we ceased to operate during that time and we know that our patients you know, really had no significant change. Vanilla, do you want to go through the, some of the data and recommendations from the ATA guidelines?<span style="color:#808080">

</span> </p> <p>Yeah, so the 2017 ATA guidelines actually corroborate the things that you've all described as occurring in clinical practice. And so the recommendations for PDC are to continue monitoring the concerning nodules sonographically each trimester. And if there's substantial growth by mid gestation, which is described as a 50 percent increase in volume, a 20 percent increase in diameter, or the occurrence of nodal metastases, or concern for nodal metastases, Then surgery is recommended and favored, particularly in the second trimester.</p> <p>And further if the nodule cancer in question appears to be stable at the mid gestational time or is diagnosed in the second half of pregnancy, as you said, John, I think the recommendation would be to operate after delivery. However, if there is concern for medullary or biopsy proven anaplastic carcinoma, which is concerning, there is a firmer recommendation to proceed to surgery at that time.</p> <p>And the additional recommendation for women with concern for MEN2 is to of course exclude the presence of a pheochromocytoma prior <span style="color:#808080">

</span> to pregnancy. We will discuss adrenal disorders at a later time. I do think you would treat medullary and anaplastic differently. It's kind of, I don't think that's, I would not view them in any way similar.</p> <p>I'd view medullary much more like papillary and anaplastic. Yeah, I think the important part is risk stratification and determining how fast the cancer is growing. I think any cancer where you're seeing growth during the pregnancy, I would consider it. Operating on the patient and so that's going to include something like Anaplastic thyroid cancer or poorly differentiated thyroid cancer.</p> <p>Okay. Well, we said at the beginning that, that good multidisciplinary communication is key in these cases. So, Priya, how do you work with the OB team in these cases? So, I try to communicate with the OB team at several different points. So first, I think the most important point is to communicate with the OB team to determine the risk to the patient and the <span style="color:#808080">

</span> fetus about operation versus not operation and what the disease process is.</p> <p>So, with a thyroid cancer or with Graves disease, what is going to be the risk to the fetus in terms of, you know, if it's Graves disease, how How well controlled the hormones are, and then on the cancer side, if the cancer is progressing or not. I think the other time to talk to the OB the OB team, and I think it's a good idea to do, include multiple members of the care team, not just the OB team, is to plan the operation.</p> <p>So if there is going to be an operation I like to have a multidisciplinary meeting and just do a dry run of what the operation is going to involve, and include if there is going to be a problem, how we're going to deal with the problem. So when is the monitoring going to be, when is fetal monitoring going to be placed?</p> <p>If there's an issue during the operation with fetal monitoring, what will be the next steps how to deal, like, are we going to stop our operation? And then we're going to. have the belly already prepped if that's necessary, et cetera. We <span style="color:#808080">

</span> kind of try to do a dry run based on where the patient is in pregnancy beforehand so that we can know what the plan is going to be in the event of an adverse event.</p> <p>Yeah, so I think the other thing that I think about is the, you know, complication side of things, and hypocalcemia is not uncommon in these patients, and you have to think about it's not just the mother, it's the fetus as well, and what significant hypocalcemia is going to do to the fetus, so, something else to consider, which leads us into our next topic here.</p> <p>Before we leave talking about thyroid surgery in pregnancy, I do want to mention that another resource is the American Association of Endocrine Surgeons. guidelines on, on thyroid surgery and that is available on the AAES website at www. endocrinesurgery. org under the resources tab.</p> <p>So let's shift gears and start talking about primary hyperparathyroidism. This is gonna reference <span style="color:#808080">

</span> clinics and endocrinology and metabolism. Alright, Vanilla, you wanna start us off on this by highlighting the physiologic changes during pregnancy impacting calcium and parathyroid homeostasis. Yeah, so due to all the substantial endocrinologic state changes in pregnancy, there are a lot of differences in regulation of calcium homeostasis in the pregnant patient.</p> <p>So due to the natural expansion of plasma volume, there is a reduced level of albumin and therefore a decrease in total calcium values in, in the gestating patient. And while there is fetal bone mineralization Considerations of maternal vitamin D levels are very critical for a direct reflection of fetal vitamin D status.</p> <p>And due to all the symptomatology of pregnancy, polyuria, fatigue, nausea, and how that kind of mimics The symptoms of hypercalcemia, actually detecting hypercalcemia can be pretty difficult because many pregnant patients experience these symptoms routinely. <span style="color:#808080">

</span> And so that is one thing to consider on the differential.</p> <p>We do get routine laps in pregnancy initially and so that may pick these things up. But another thing to consider is pseudo hyperparathyroidism due to elevated hyperparathyroidism. PTRH related peptide levels, which occur related to the expanding and growing placenta, as well as enlarging breasts during pregnancy.</p> <p>And these things are not without risk. We do worry in pregnancy in the gravid patient about long standing hypercalcemia risks. So these risks include hypercalcemic crisis, nephrolithiasis, and impairment of renal function, as well as preeclampsia. We do worry additionally about impacts on the fetus particularly intrauterine polyhydramnios.</p> <p>And then after birth due to lack of development of the parathyroid glands in a patient where there's maternal hypercalcemia, we worry about dysregulation in the neonatal parathyroid gland, tetany, and ultimately we worry about death of the infant or intrauterine fetal death. <span style="color:#808080">

</span> And what about diagnostic modalities and treatment when you, when we see these patients?</p> <p>So, similar to with any patient, we do get a good history in physical and we also consider the potential for family history, looking for potential genetic syndromes. Often times these patients are usually under 40. In looking at biochemical diagnoses, one thing that confounds the diagnosis is that urine calcium can increase in pregnancy as a normal physiologic response.</p> <p>And this is reflected in some of the European Society data we'll review later. So, do we do anything different during evaluation? Do we check ionized calcium levels more than serum calcium levels? Do we check PTHRP levels routinely? So, because of the differences in total calcium levels and reduced albumin levels, we do use ionized calcium levels as a marker in pregnant patients.</p> <p>Preferentially over serum calcium levels. Because of the confounding parathyroid hormone related peptide there's not really a consensus in measuring those <span style="color:#808080">

</span> levels routinely, and so that further confounds the diagnosis of hyperparathyroidism in pregnancy. So there is always an option if there is clinical concern to do a forward land exploration.</p> <p>But we, you know, would like to minimize the extent of dissection and prolonged surgery in a pregnant woman if possible. And so attempting localization is reasonable and we do have that technology today. So I'd start, I think, with a neck ultrasound in a patient that's pregnant. Clearly CT or any use of ionized contrast is contraindicated.</p> <p>For more information visit www. FEMA. gov And so, the option of a 4 DCT here is limited. And so, you can use a cestamib scan with dose reduction that is feasible. And, if necessary, you can also use MRI, because that doesn't have any ionizing radiation. So, that is one consideration. But I think I'd start with a good old fashioned neck ultrasound.</p> <p>Alright so, in, you know, would medical management be be indicated in any of these vanilla? And if so, <span style="color:#808080">

</span> what potential medications could be used in other conservative management strategies? So, Conservative management approaches like oral and IV hydration are certainly options throughout the pregnancy to maintain hypercalcemia.</p> <p>With respect to medications, the juries out on SinoCal said there is some data that suggests it is safe in pregnancy but it is nebulous at this time. However, we do know that bisphosphonates and danosumab are contraindicated in pregnancy, and so our options in pregnancy here are limited due to fetal risk.</p> <p>Okay, and then obviously we have surgical management, and if we can keep to a directed or focused approach that's great. But certainly if you need to do a foregland exploration that's obviously been the gold standard for a long time, and certainly something that we all should know how to do.</p> <p>Priya, why don't you tell us a little bit about your decision making regarding conservative treatment versus parathyroid <span style="color:#808080">

</span> surgery in pregnancy. I think the couple of things that drive my decision making for that are the level of the calcium and the level of the PTH more so the level of the calcium.</p> <p>So if it's over, like with an albumin corrected level of over 11, then that's a time where I would start thinking about an operation. Whereas if it's lower than 11, then I'm less likely to consider an operation because it's more likely to be able to be medically managed. John, what about you? Yeah, I agree.</p> <p>I think when it's relatively mild disease, I would much prefer to, to manage it medically, but if it's significant, clearly causing symptoms, And I think you're bound to operate on them. Yeah. I tend to operate, I think, on, on most of them and out of concern for for the loss of the pregnancy.</p> <p>So I, I tend to be a little bit more aggressive. I do some of these under local anesthesia and haven't had any major, <span style="color:#808080">

</span> major issues. I just worry about the parathyroid development in the fetus. As well, never know exactly you know, what, what level is going to prevent or cause, cause any of those types of issues.</p> <p>So, so different strategies and all, you know, backed up by various types of data. So, Vanella, why don't you tell us a little bit about the differences in some of the papers that we pulled for this podcast. So, there are varying recommendations in terms of parathyroid surgery in pregnancy. A lot of the data that exists presently is based on observational studies and there is a systematic review of 382 patients that was performed by Sandler, et al. In an ear, nose, and throat study. journal, and they found a significantly lower complication rate for surgery versus conventional therapy. So the current literature actually strongly favors surgery, while reviews prior to 2010 offer disparate reviews. There is a European Society of Endocrinology program for parathyroid disorders, <span style="color:#808080">

</span> or PARET, and they do recommend surgery, particularly if albumin adjusted calcium is greater than 2.</p> <p>85, so they provide some more stringent criteria, and if ionized calcium levels are greater than 1. 45. And so generally speaking, the literature does vary, but the majority advise, as we've described in this podcast, favoring surgery if indicated during pregnancy. Yeah, and the numbers that you quoted are millimoles per liter, so when we translate that to the albumin adjusted calcium it's greater than 11.</p> <p>4 milligrams per deciliter in ionized calcium, which is greater than 5. 81 milligrams per deciliter, depending on what your lab uses for for values. You want to elaborate a little bit? On this and tell us about the case series by Mullen from Australia, which was published in 2010. Yeah, so Mullen et al.</p> <p>actually described a series of seven patients all pregnant women, <span style="color:#808080">

</span> between the period of 1992 to 2007, and, and there's really like a beautiful and elaborate description of each of the courses of these patients and the clinical management. And ultimately, their consensus is that maternal and fetal complications are actually difficult to predict based on the actual serum calcium level, and so those values are not necessarily predictive or reliable in terms of risk.</p> <p>And we talk a lot about risk stratification. So, they do say that when treated surgically, the overall neonatal complication rate that they found was much lower than what was documented for conservative therapy, at about 10 to 20 percent. And so, that further supports. It's the discussion of proceeding towards surgery in pregnant women with parathyroid, hyperparathyroidism.</p> <p>Alright, great. Well, I think that's been a great general overview of a topic that can be stressful for all involved. Pregnancy is a unique physiologic condition that compounds the risks inherent to endocrine disorders needing surgical treatment and the decision making can be complex.</p> <p><span style="color:#808080">

</span> Evaluation and management can be different due to maternal fetal needs and medical treatments or procedures that may have teratogenic effects or increase risk of fetal demise. Surgical decision making must balance the risks and benefits to the mother and the fetus. Thanks for joining us and stay tuned for part two of endocrine disorders in pregnancy.</p> <p>Donate the day!</p> </body> </html>