Hello, everybody. Welcome to our next session entitled Managing Thyroid Disease in Pregnancy. My name is Matthew Levine. I'm an endocrinologist and the Endocrinology Fellowship Program Director at Scripps Clinic in San Diego. And I will be serving as your moderator today. The speaker for today's session is Dr. Spiruta Maraca. Dr. Maraca is an endocrinologist and clinician scientist at the University of Arkansas Medical Sciences and the Central Arkansas Veterans Healthcare System. She is an assistant professor of medicine as well at the University of Arkansas, where she is also serving as the Endocrine Fellowship Program Director. She completed her residency in internal medicine at the University of Connecticut and post-graduate fellowship in endocrinology at the Mayo Clinic Rochester. During her post-graduate training, she also obtained a master's degree in clinical and translational science. She is a co-founder of the Knowledge and Evaluation Research Unit in Endocrinology at Mayo Clinic, where she holds an appointment as a research collaborator in the Division of Endocrinology. Dr. Maraca's research is focused on thyroid disorders, including hypothyroidism in pregnancy. Her work has been published in high-impact journals with over 1,000 citations, including those referenced in national and clinical practice guidelines. Dr. Maraca. Good afternoon. I'm very honored for the invitation to participate in Envision, the ACE Annual Virtual Meeting 2021. This presentation is on managing thyroid diseases in pregnancy, which is a rather broad topic. I chose a few areas to focus on, and my goal is that upon completion of this presentation, you will be able to recognize and manage thyroid dysfunction in pregnancy, discuss current controversies regarding therapy for thyroid dysfunction, and assess thyroid nodules in pregnant women. I have nothing to disclose. First, I would like to briefly review the adaptations of thyroid physiology in pregnancy. Understanding these changes is crucial for the interpretation of thyroid function tests in pregnancy. During pregnancy, the placenta is producing the hormone human chorionic gonadotropin, well known as HEG. Both TSH and HEG are glycoproteins that consist of two subunits. The alpha subunit of HEG is nearly identical to that of TSH. Although they have distinct beta subunits, and there is a 38% sequence identity there too. This homology between HEG and TSH results in cross-reactivity. Therefore, HEG can bind at the TSH receptor and stimulate the thyroid for thyroid hormone production. This is a simplified representation of what happens to the thyroid physiology during pregnancy. As we discussed, due to the similarity of HEG with TSH, HEG stimulates the thyroid, and free T4 levels increase sharply in first trimester, while pituitary in feedback decreases the TSH secretion. Estrogen increases thyroxine binding globally in levels up to 2.5 times from initial values, which leads to an elevation in total T4 levels and further decrease in the TSH levels. In the early stages of pregnancy, a transient period takes place during which T4 and TPG concentrations are constantly changing until reaching a plateau around mid-gestation. Ultimately, only 0.03% of serum T4 remains unbound, and more thyroid hormone production is needed to maintain adequate free T4 levels. In addition, thyroxine metabolism increases due to placental deodenase 3 activity, contributing to the need for increased production of thyroid hormones. Finally, there is increased renal iodine clearance, and it is estimated that the daily iodine requirements increase by 50% during pregnancy. Now, studies have shown that depending on the iodine intake, thyroid volume may increase during pregnancy by 10% in normal at higher iodine intake areas, and up to 40% in low iodine intake areas. Epidemiological data suggests that low iodine intake could predispose to the development of thyroid dysfunction and thyroid nodules in pregnancy. Therefore, it is highly recommended that supplement with 150 micrograms of iodine daily in the form of potassium iodide should be taken throughout pregnancy. So, pregnancy is in essence a stress test for the thyroid that could result in maternal hypothyroidism. However, it is important to remember that as for many other endocrine disorders, there is a spectrum of thyroid hyperfunction. Between euthyroidism, where there is normal TSH and T4, and overt hypothyroidism, where TSH is elevated with low T4 levels, found in about 0.5% of pregnancies, we have the subclinical hypothyroidism, where the TSH elevation is adequate to keep the thyroid hormone production normal. The prevalence of subclinical hypothyroidism varies significantly, with a recent meta-analysis estimating at about 3.5% on average. And of course, there is the entity of isolated hypothyroxinemia, characterized by normal TSH and low T4 concentrations, for which we're still struggling to find a place in this spectrum. If during pregnancy, the expected mother has untreated overt hypothyroidism, it has been well-documented that it can lead to increased risk of maternal and fetal complications. So, overt hypothyroidism in pregnancy has been associated with pregnancy loss, gestational hypertension and preeclampsia, placental abruption, preterm delivery, low birth weight, and perhaps more importantly, with decreased offspring cognitive function. Due to all these risks, it is clear that we need to treat maternal overt hypothyroidism. For choosing the optimal method of treating hypothyroidism in pregnant women, it is important to remember that the delivery of T4 is crucial for the developing fetal brain, and that fetal CNS is relatively impermeable to T3. So, patients using desiccated thyroid or T3, T4 combination therapy are likely at risk for having insufficient transfer of maternal T4 to the fetal brain. So, levothyroxine is the recommended treatment of choice for maternal hypothyroidism. Regarding levothyroxine monitoring, TSH should be checked every four weeks until mid-gestation and at least once near 30 weeks unless there is further dose adjustments. And it's reasonable to target TSH in the lower half of trimester specific reference rates or less than 2.5 if you are using a fixed cutoff. The importance of adequate thyroid hormone replacement during pregnancy is well demonstrated by this retrospective simple center study. We identified 96 pregnant women with history of levothyroxine-treated hypothyroidism who had a TSH more than 2.5 with international units per liter in the first trimester. And we noted that for those women that levothyroxine dose was increased the pregnancy loss was 2.4% versus 36.4% for those that for whatever reason the levothyroxine dose stayed stable. And this was a confirmation from consistent with other previous studies. Other pregnancy-related adverse outcomes were similar between groups. Up to 85% of levothyroxine-treated hypothyroidism and up to 80% of levothyroxine-treated hypothyroid women before conception will need an increase in their levothyroxine dose during pregnancy of about 25 to 50%. The amount of levothyroxine increase depends on the etiology of hypothyroidism and it's typically higher in radioiodine or surgery-induced hypothyroidism. Now in the unlikely event that a new diagnosis of overt hypothyroidism takes place in pregnancy we dose levothyroxine with 2.33 micrograms per kilogram per day. For uteroid women receiving once daily dosing of levothyroxine, a recommendation to take two additional tablets weekly immediately after confirming pregnancy it can effectively mimic gestational physiology and prevent maternal hypothyroidism. So during this critical time of first trimester this protocol can prevent maternal TSH elevation more than 2.5 million international units per liter in 85% of pregnant women and more than five in all pregnant women. The safety of this profile was found to be superior to that of an increase of three additional tablets per week. Now, after delivery levothyroxine dose can be reduced to the patient's preconception dose. For those women who were started on levothyroxine due to subclinical hypothyroidism in pregnancy levothyroxine can potentially be discontinued especially if the levothyroxine dose was less than 50 micrograms per day or the TPO deboding status was negative. So in a study that we conducted a few years ago that 50% of pregnant women with subclinical hypothyroidism who were started on levothyroxine supplementation were able to discontinue treatment at the end of pregnancy. And after that thyroid function testing should be performed about six weeks postpartum to assess the thyroid status. In contrast to the well-known negative impact on pregnancy over hypothyroidism for pregnant women with subclinical hypothyroidism the data are less clear and even less for those with isolated hypothyroxinemia. So the question that we are left to answer is the following. Are these real diseases requiring treatment or are there's just biochemical diagnosis of no clinical consequences? Well, in order to answer this question given all the changes in thyroid physiology during pregnancy, it's important to know what the normal TSH range in pregnancy is. Former guidelines by the American Thyroid Association used a TSH of 2.5 as the upper normal limit for the first semester and three for the second and third semesters. Endocrine Society used similar TSH cutoffs. However, these cutoffs were based on the fact However, these cutoffs were based on studies involving about 5,000 patients but results from many population studies with total number of patients more than 50,000 actually suggest that the upper TSH limit in pregnancy is not as low as previously suggested by the guidelines but closer to the range of four to five meter naltronal units per liter, raising the concern for over diagnosis of subclinical hypothyroidism if a TSH upper limit of 2.5 is used. So taking into consideration these latest epidemiological findings the 2017 updated ATA guidelines still strongly recommend to use a laboratory or population-based pregnancy specific TSH reference range. However, if this is not available as commonly the case now an upper limit of four may be used which usually corresponds to a reduction of about 4.5 meter naltronal units per liter compared to the non-pregnant TSH range. Now, the measurement of maternal Pt4 is complicated by many factors related to the physiological changes during pregnancy and Pt4 immunoassay values can be misleadingly low during pregnancy. Using direct Pt4 measurements such as with mass spectrometry may be more accurate but it can be expensive, time-consuming and not widely available. So due to these issues with immunoassays in pregnancy the ATA guidelines, if a immunoassay is used an assay method specific and trimester specific pregnancy reference rates should be applied. In lieu of measuring Pt4, total Pt4 measurement with the reference range adjusted for pregnancy can be used to assess the thyroid hormone levels. Gestation week values can be calculated as 5% above the normal per week in weeks seven to 16 and 50% above the normal for week 17 and until the end of pregnancy. Accurate estimation of the Pt4 concentrations can also be done by calculating a Pt4 index. With this in mind, I believe you would agree that our confidence in diagnosing isolated hypothyroidism anemia in the setting of normal TSH concentration and Pt4 concentrations below the 2.5th or 5th percentile is limited. And this is reflected in the current literature where the prevalence of isolated hypothyroidism anemia ranges from 1.3 to 26% depending on the Pt4 lower limit cutoff use or the iodine status of the population, the gestational age at the thyroid hormone testing or the ethnicity. So the next reasonable question that you may have is what adverse outcomes are associated with subclinical hypothyroidism and isolated hypothyroidism anemia? Basically, why do we really care? To summarize the available evidence, we performed a systematic review and meta-analysis including 18 cohort studies comparing 4,000 pregnant women with subclinical hypothyroidism to uteroid pregnant women. These studies were at low to moderate risk of bias mainly due to limitations regarding how representative the study population was, lack of blinding when assessing the outcomes and lack of adjustment for confounders. We also noted that there were significant differences in terms of how subclinical hypothyroidism was defined and when the thyroid function tests were done. We found that pregnant women with subclinical hypothyroidism were two times more likely to have pregnancy loss and 2.6 times more likely to suffer neonatal death compared to uteroid women. They were also at higher risk for placental abruption and premature rupture of membranes. There were no differences in other important adverse pregnancy outcomes. However, it is important to remember that association doesn't mean causation. And another thing to remember is that the possibility of publication bias whereby negative studies are less likely to be published and therefore are not included in analysis like this. In 2019, Dr. Koribar and collaborators from the Consortium on Thyroid and Pregnancy performed this first meta-analysis of individual patient data from 19 prospective cohort studies, including about 47,000 pregnant women. They found that subclinical hypothyroidism and isolated hypothyroxinemia were significantly associated with preterm birth. Notably, all analysis were adjusted for important confounders. Another study from this group meta-analyzed individual participant data from 20 cohort studies, including more than 48,000 child pairs. And this study found that subclinical hypothyroidism was associated with a lower mean birth weight than uteroidism. There was also higher risk for gestational age than compared to uteroid women. Again, analysis was adjusted for important confounders. On the other hand, isolated hypothyroxinemia was associated with higher birth weight. And more interestingly, the authors noted that the higher the 3T4, you can see that there was a inverse dose relationship. And higher 3T4 concentrations was associated with lower birth weight. This result has significant implications as it prompts for careful consideration of potential risks of levothyroxine therapy and over-treatment during pregnancy. Moving now to the effect of subclinical hypothyroidism on cognitive function of offspring. This study published in 1999 received significant attention. Children from seven to nine years old of 48 untreated hypothyroid mothers were compared to those of 124 matched controls. And the children of the hypothyroid mothers had significantly lower IQ. However, you can see that the majority of hypothyroid women had a TSH more than 10, which would classify them as having overt hypothyroidism rather than subclinical hypothyroidism with our current diagnostic criteria. Nevertheless, this recent systematic review and meta-analysis show that both subclinical hypothyroidism and isolated hypothyroxinemia are associated with higher risk for child intellectual impairment. To make things more interesting, having positive TPO antibodies is considered a synergistic risk factor for adverse pregnancy outcomes. In this prospective cohort study from China, more than 3,000 women were screened for thyroid dysfunction and pregnant women with a high TSH levels were 3.4 times more likely to experience a miscarriage compared to euthyroid women. And this risk tripled for women who also had positive TPO antibodies suggesting this synergistic effect. So given that many observational studies show that women with subclinical hypothyroidism and even isolated hypothyroidisemia can have adverse pregnancy outcomes compared to the ones with normal thyroid function, should we be prescribing thyroid hormone treatment for these pregnant women? Well, the answer has not been straightforward. Taking the example of subclinical hypothyroidism, the American Congress of Obstetricians and Gynecologists in 2007 found insufficient evidence to recommend treatment. Then ATA in 2011 recommended to treat pregnant women with subclinical hypothyroidism, but only if they have positive TPO antibody levels. And one year later, the Endocrine Society published their recommendations of universally treating all pregnant women with subclinical hypothyroidism, acknowledging that this recommendation was based on low quality evidence. So let's review the evidence regarding the effectiveness of levothyroxine therapy in preventing adverse outcomes in pregnant women with subclinical hypothyroidism and isolated hypothyroidisemia. This prospective study from Negra and colleagues was widely cited in the 2011 and 22 guidelines, 2012 guidelines, I'm sorry. And in this study, about 4,500 women were randomized by the 11th week of pregnancy to universal screening for thyroid dysfunction versus case finding based on the presence of risk factors for thyroid disease. All pregnant women at the universal screening were checked for thyroid dysfunction and started on levothyroxine therapy if they were found to be hypothyroid defined as a DSH of both 2.5 milliliter national units per liter and positive TPO antibodies. From the case finding group, only the high risk women were checked whereas the low risk group had their serum stored and checked at the end of pregnancy. Therefore, these 34 hypothyroid women never received therapy. The primary outcome for the study was a composite endpoint of 18 obstetrical and neonatal complications with variable importance which makes the interpretation of the results challenging. There was no significant difference between the total number of adverse outcomes in the universal screening and the case finding group. But considering only the cohorts of low risk men represented by the green bars here in the graph, complications were less likely to occur among women in the universal screening group than the women in the case finding group driven by the events happened to the undetected and untreated hypothyroid patients. However, as I showed you, the non-treated group was a substantially smaller group and this study was profoundly underpowered for this. Now, this study published in the New England Journal of Medicine had a similar design. About 22,000 women were randomized at 12 weeks of gestation to a screening or control group. And treatment was started on average at the 13 gestational week if the TSH was above the 97.5th percentile or the 54 below the 2.5th percentile or both. This study found no difference in the IQ of children at three years of age and also the number of children who had an IQ less than 85. A subgroup analysis, including only the women meeting the criteria for subclinical hypothyroidism or isolated hypothermia had similar results. The study received criticism that levothyroxine was started too late in gestation to have any major influence on brain development. Moreover, it was questioned if we can accurately measure IQ in a three-year-old child. However, the follow-up study of CATS-2 showed no difference in child cognition at the mean age of 9.5 years, confirming the original findings. Also, in light of data suggesting an inverse relationship of pretty poor with neurocognitive function, another concern was that the lack of difference between groups was due to the really high starting dose of 150 micrograms of levothyroxine. About four years ago, the results of a multicenter randomized trial funded by NIH were released. Pregnant women with TSH more than four and normal at the four levels were randomized to levothyroxine treatment versus placebo. The primary outcome of the trial was IQ score of offspring at five years, and this study found no difference between groups. However, similarly to the CATS study, levothyroxine was actually started at the second trimester. They also looked into selected adverse pregnancy outcomes and found no difference between treated and untreated women. Similar results were also seen in levothyroxine treated versus untreated pregnant women with isolated hypothyroxinemia. Around the same time we published at the BMJ the results from the first national study in the United States, using a large national database, we were able to identify 843 pregnant women with subclinical hypothyroidism who received thyroid hormone treatment and compared to about 4,500 women who didn't. The treated women had 38% less risk for pregnancy loss compared to the untreated women. However, as you can see, thyroid hormone treatment was associated with increased risk for preterm delivery, gestational diabetes, and preeclampsia. Looking at the data more carefully, we were able to show that the treated women with higher pretreatment TSH level between 4.1 and 10 were the ones who had the benefit of fewer pregnancy losses and not the ones with milder TSH elevation. So this lack of benefit, together with the noted risk of adverse events, raised the concern of possible overtreatment for women with a TSH between 2.5 and four. So based on all this new available evidence, the American Heart Association treatment recommendations for subclinical hypothyroidism recently changed. Taking into account the additive risk of having positive TPO antibodies, the recommendations are stratified by antibody status. So for TPO antibody positive women, when TSH is between the upper limit of the reference range and 10, or if you use fixed cutoff between four and 10, levothyroxine treatment is recommended, typically with a dose of about 50 micrograms per day. For the same reference range in TPO antibody negative women, levothyroxine can be considered. Now, when TSH is between 2.5 and four and a woman has positive TPO antibodies, again, levothyroxine treatment can be considered, especially if there are some certain risk factors, but no treatment is indicated for women who are TPO antibody negative. Finally, given the existing interventional data, treatment of isolated hypothyroxinemia is not currently recommended. Since the publication of these guidelines, some groups have challenged the strength of treatment recommendation regarding the TPO antibody negative pregnant women who have a TSH between four and 10. So this study from Nazarpur and colleagues was a well-contacted small randomized controlled trial that showed that for TPO antibody negative women, when TSH is four or above, there was some benefit in terms of preterm delivery where levothyroxine therapy was associated with 60% less risk to experience preterm delivery. And similarly, the Tehan-Tarui study showed a decrease in the rates of preterm delivery and neonatal hospital admissions for TPO antibody positive women when TSH is four or above. And I would like to close this part of the presentation with this recent study that challenged the common notion that levothyroxine is an easy pill to take. This was a tertiary academic medical center survey of 64 hypothyroid pregnant women on levothyroxine, most of whom were diagnosed before pregnancy. And we found that one in three pregnant women had a feeling of uneasiness or anxiety due to their hypothyroidism diagnosis. And 45% reported not receiving an explanation regarding the maternal fetal risks of uncontrolled hypothyroidism or the benefits of adequate control. In fact, they asked us for educational material at the end of the survey, suggesting that maybe we need to do a better job educating our patients regarding this. More interestingly, two in three patients expressed various concerns of levothyroxine related treatment burden. The most common complaint was that they had to take the pill on an empty stomach. Switching gears now, let's discuss about hyperthyroidism in pregnancy. Although subclinical hyperthyroidism has not been associated with adverse pregnancy outcomes, poor control of thyrotoxicosis is associated with plenty of complications like pregnancy loss, pregnancy-induced hypertension, preeclampsia, prematurity, low birth weight, intrauterine growth restriction, and even maternal congestive heart failure. The offspring can experience neonatal hypothyroidism, even fetal hyperthyroidism. And there are some studies suggesting that fetal exposure to excessive levels of maternal thyroid hormone may program the offspring to develop diseases such as seizure and neurobehavioral disorders later in life. Overt hyperthyroidism in pregnancy is diagnosed based on a TSH concentration lower than the reference range and thyroid hormone levels higher than the pregnancy-specific or adjusted reference range. However, it's important to remember that in the first semester, the lower reference limit for TSH can be reduced by about 0.4 mid-10 nursing units per liter, which is equivalent of about TSH of 0.1. And this gradually returns towards the non-pregnant range in the second and third semesters. We always need to remember to ask for biotin intake as a biotin of more than five to 10 milligrams per day, micrograms per day can cause interference with the assays and give incorrectly the biochemical picture of hyperthyroidism. Also in contrast to the non-pregnant population, thyroid uptake and scan is contraindicated in pregnancy. One of the most important decisions in the management of hyperthyroidism in pregnancy is whether aditheroid drug therapy is required. The answer to this question first depends on the cause of hyperthyroidism. The most common causes of hyperthyroidism in pregnancy is gestational transient thyrotoxicosis with an estimated prevalence of about two to 11%, followed by Graves' disease with a prevalence of 0.2%. Other causes such as toxic adenoma or subacute thyroiditis are extremely uncommon and we will not discuss them here. There are certain characteristics that can help the clinician differentiate between Graves' disease and gestational transient thyrotoxicosis. For example, in contrast to Graves' disease, women with gestational transient thyrotoxicosis typically don't have family history of Graves' disease or other autoimmune disorders. It is commonly found in the first semester whereas Graves' disease can be diagnosed at any time during pregnancy. Women with hyperemesis or multiple gestation are more likely to have gestational transient thyrotoxicosis. Women with GDT also have no symptoms often or even just mild signs of hyperthyroidism whereas women with Graves' disease with a careful history, you can find that they have symptoms or signs already before pregnancy. Women with Graves' disease could also have positive TRAB or TPO antibodies and potentially other manifestations of Graves' disease such as orbitopathy. I would add here that the ratio of serum T3 to T4 of more than 20 to one is also suggestive of Graves' disease. For women with GDT, the other thyroid drugs are not indicated because the course of the disease is self-limited and the serum T4 typically returns to normal by week 14 to 18. Obstetrical outcome has not improved in isolated cases where actually these women were treated with ADT. So we monitor with physical exam and repeat thyroid function tests every three, four weeks. In situations where there's excessive hyperadrenergic symptoms, we can use a short course of beta blocker therapy usually with propranolol, avitalol or metoprolol. We avoid atenolol as this has been associated with fetal growth retardation. Also if there's hyperemesis, we can have supportive measures to treat dehydration and so on. Now for women with Graves' disease, ADT therapy and beta block therapy is often required. In addition to the usual side effects seen in non-pregnant patients, adithyroid drugs have potential pathogenic effects in pregnancy. Methimazole or carbamazole-briobathine has been well-described, including aplasia crutis, cranial or esophageal atresia and other congenital malformations. And it has been shown to affect about 9% of children who have exposure to methimazole in early pregnancy. Now PTU was previously considered a safer medication for use during cessation. However, this Danish study revealed that 8% of children exposed to PTU develop birth defects associated with this therapy, mostly face and neck cysts and urinary tract abnormalities. But because they are considered less severe, there is recommendation to use PTU in the first semester during the critical time of organogenesis, despite the PTU risk of hepatotoxicity. However, it's worth noting that in the small group of women who changed from methimazole to PTU during pregnancy, there was no indication of amelioration of the birth defects. And this emphasizes the importance of treating Graves' disease with a definitive treatment or at least shifting to PTU already when pregnancy is entertained for a woman with pre-existing Graves' disease. But we need more studies in this field. Now, recommendations for Graves' disease management have small differences depending on whether the diagnosis is newly made during pregnancy or we're dealing with a pre-existing Graves' disease. So for women diagnosed with thyrotoxicosis during the first semester of pregnancy, we recommend starting antithyroid drug therapy with PTU. If ATD therapy is required after the 16 weeks of gestation, it really remains unclear whether PTU should be continued or therapy changed methimazole. As both medications are associated with potential adverse effects and shifting potentially may lead to a period of less tight control. And having in mind the hepatotoxicity of PTU, there's no official recommendation at this point about switching from one to the other. Now, if Graves' disease is diagnosed after the first semester, it's a bit more straightforward. We can start directly with methimazole. Tribodyl body level is obtained at baseline for diagnosis. And if elevated as expected, we repeat at 18 to 20 weeks. Tribodyl will disclose the placenta and can cause fetal hyperthyroidism. So fetal monitoring will be required if elevated. And we will repeat at 30 to 34 weeks since elevated tribo level then can identify babies at risk for neonatal hyperthyroidism and the need for postnatal monitoring. We also check tribo if mother is still taking antithyroid drug in the third trimester. Thyroidectomy may be indicated for certain situations such as cases of allergies or contraindications to antithyroid drug therapy. And if need be, we typically want to do this in the second trimester. Now, for women with preexisting Graves' disease currently taking methimazole, it is recommended to switch to PTU as soon as pregnancy is confirmed until at least 16 weeks or withdraw antithyroid drug therapy if the patient's a good candidate as I will show you later. Tribody body testing and indications for thyroidectomy are the same with what we just discussed. Now, for those with history of Graves' disease in remission after stopping ATD therapy, we perform thyroid function tests to confirm euthyroidism and tribody body check is not needed. If a woman had previous treatment with radiofibridine or surgery for Graves' disease, we still measure TRAB initially during the first semester and if elevated again up to 22 weeks and 30 to 34 weeks of gestation. The period of major risk of birth defects caused by intake of medication pregnancy is gestational week six to 10. So if we withdraw ATD therapy before week five, perhaps we can prevent birth defects caused by ATD exposure. We consider that the risk for relapse is low for women where the threonomide dose is low, the tribody body level is low or undetectable, having normal TSH levels, duration of threonomide therapy of more than six months, and no evidence of active ophthalmopathy or large scoilers. So these women could be candidates of therapy withdrawal. And in that case, we follow with third function testing and physical exam every one to two weeks during the first semester, and everything is stable every two to four weeks during the second and third semester. And in this way, with this frequent third function testing, we will be able to detect early any relapse and initiation of adenovirus drug therapy, and really the risk of this transient and mild hyperthyroidism, if it occurs, is really negligible to the mother and the fetus. When shifting from methimazole to pitium, a dose ratio of approximately one to 20 should be used, also because the half-life of PTU is considerably shorter than that of methimazole, the dose of PTU should be split over the day. We aim to treat with the lowest possible dose of adenovirus drug therapy to keep the mother's hormone levels at or slightly above the reference range in pregnancy to avoid fetal hyperthyroidism. So for example, normalization of maternal TSH is not the goal of treatment, and it could indicate excessive ATD dosing to the fetus, and therefore ATD dose will need to be reduced in this case. Third function should be assessed at least every four weeks and the ATD dose adjusted as required. And in the third semester, about one third of patients that were still requiring ATD can actually have the therapy discontinued because of disease remission. We do not recommend block replacement therapy consisting of ATD plus levothyroxine in pregnancy as this can increase the risk for fetal goiter and hyperthyroidism, and the exception to this is only for treating isolated fetal hyperthyroidism. Which brings me back to the fetal surveillance for hyperthyroidism during pregnancy. It is indicated for women who have uncontrolled hyperthyroidism in the second half of pregnancy or have high TRAB levels at any time during pregnancy. Consultation with an experienced obstetrician or maternal fetal medicine specialist is important at this setting, and the fetal monitoring includes heart rate, growth, amniotic fluid volume, and goiter. And a few words for the nursing mothers. We should know that both methimazole and PTQ appear in the breast milk in small concentrations. The use of ATDs in doses up to 20 milligrams per day for methimazole or 450 milligrams per day for PTU immediately after a feed seems to be safe without affecting the infant thyroid function, growth, or IQ. No routine screening of the infant's thyroid function is required, and due to the potential for hypotoxicity with PTQ, a methimazole is the preferred agent. Now, for the last part of this talk, I would like to discuss briefly the assessment of thyroid nodules in pregnancy. The prevalence of thyroid nodules in pregnancy varies between 3% and 21% and increases with increasing parity in age. So it is likely that you will encounter a pregnant woman with thyroid nodule perhaps more often than the pregnant women with thyrotoxicosis. It is uncertain if thyroid nodules discovered in pregnant women are more likely to be malignant than those found in non-pregnant women since there are no population-based studies to address this question. Three retrospective studies from the 80s and 90s have reported an increased risk of malignancy in pregnant women with thyroid nodules with prevalence up to 43%. However, these studies had a significant patient selection bias because they were conducted in tertiary reference hospitals where women with cancer may be overrepresented. In this prospective study by Kung, no pregnant women with thyroid nodules had thyroid cancer. And finally, this study by Smith was a retrospective analysis of all obstetrical deliveries in California from 1991 through 1999. And the prevalence of thyroid cancer was 14.4 per 100,000 and with most cases diagnosed within one year postpartum. Generally, the diagnostic strategy for thyroid nodules is similar in pregnant and non-pregnant women with the exception that radionuclide scans are contraindicated to pregnancy as they can lead to fetal irradiation or hypothyroidism. Upon discovering a thyroid nodule, a complete family and personal history, a clinical examination, thyroid function tests and thyroid ultrasound should be performed and if indicated, an FNA should be considered. All pregnant women with thyroid nodules who have a TSH measurement performed and if thyroid function tests are, if TSH was low for pregnancy range, then thyroid hormone levels are checked to rule out ferotoxicosis. And for women with suppressed serum TSH, beyond the 16 week of gestation, FNA of a clinically relevant nodule should be deferred until after pregnancy where at that point, radionuclide scans can be done to evaluate the thyroid nodule function. Calcitonin level may be considered for women who have a high risk for medullary thyroid cancer and as a non-pregnant population, feroglobulin testing is not indicated. In the latest guidelines for management of thyroid nodules in pregnancy, a thyroid nodule FNA is generally recommended for newly detected thyroid nodules in pregnant women with non-suppressed TSH. Determination of which nodules require FNA should be paced about the nodules sonographic pattern. However, since overall survival, as I'll show you later, doesn't differ if surgery is performed during or after gestation in patients diagnosed with thyroid cancer during pregnancy, patient preference for timing of FNA should be considered. So proceeding with FNA in the context of pregnancy should not be an automatic immediate action. The decision should take into account the clinical context, including the patient's concern and anxiety, risk factors for thyroid cancer and the clinical setting. So considering these and the patient's overall goals of care a dialogue between clinician and the patient should be used to agree on a patient-centered diagnostic plan. Now for women who proceed with FNA and found to have benign cytology, no special surveillance strategies are needed. Depending on the suspicion for malignancy, thyroid ultrasound can be repeated within 12 to 24 months after pregnancy is completed. And if there is clinically significant growth or development of new suspicious features, FNA could be repeated. Now in pregnancy, even more indeterminate cytology represents a diagnostic dilemma. Although diagnostic surgery provides definitive identification of cancer if present, avoiding surgery when possible during pregnancy is preferable. So pregnant women with cytologically indeterminate thyroid nodules may be followed conservatively during pregnancy, especially since there are no prospective studies evaluating the prognosis of these women. And because the majority of these nodules are actually later found to be benign, and even when cancers often represent less aggressive variants of thyroid cancer. So based on these per ADA guidelines, women with cytologically indeterminate nodules in the absence of cytologically malignant left nodes or other signs of metastatic disease do not regularly require surgery while pregnant. And a surgery could be considered if there is clinical suspicion for an aggressive behavior in cytologically indeterminate nodules. And it's worth noting that molecular markers are not validated in pregnancy, and it is possible that changes in nodules' RNA expression may occur during gestation, altering the performance of RNA-based gene expression tests. Less likely for DNA-based tests, but nevertheless, molecular testing is not recommended during pregnancy for indeterminate nodules. Now, what happens if a woman is diagnosed with thyroid cancer during pregnancy? This is the second most common cancer in pregnancy represented by breast cancer. 10% of all thyroid cancers occur during childbearing age, are diagnosed during pregnancy or within one year of delivery, and the most common histological type is capillary. Management should involve a multidisciplinary team, including endocrinologists, surgeons, OB, radiologists, and neonatologists even. Whether pregnancy has an impact on the progression and prognosis of newly discovered differentiated thyroid cancer and whether it confers a higher risk of recurrence later remains a heated debate. This is mainly due to the limited number of available studies addressing these issues, many of which were conducted decades ago, focused on PTC and also the lack of randomized control trials. So most studies suggest that pregnancy does not worsen the prognosis of women diagnosed with differentiated thyroid cancer, and there's also a consensus among all studies that timing of surgery, be it during pregnancy or postpartum, does not affect survival. This study from Dr. Ito's group provides further reassurance. Out of 50 pregnant women with preexisting capillary microcarcinoma, only four had growth with only two proceeding with thyroidectomy. None of the women developed nodal metastatic disease during pregnancy. So despite growth of some papillary microcarcinomas during pregnancy, these patients continue to have an excellent prognosis. And I try to summarize here the management considerations for women diagnosed with thyroid cancer in pregnancy, the impact of pregnancy on women with newly diagnosed anaplastic or medullary carcinoma is unknown, so delay is likely to adverse affect the outcome, so immediate surgery should be considered. Similarly, if there are severe compulsive symptoms. Now, thyroidectomy may be delayed in most pregnant patients with differentiated thyroid cancer until the postpartum period. And in this case, women can be followed with a thyroid ultrasound every trimester and thyroid function test every month. If the patient's TSH is more than two, it may be reasonable to initiate levofloxacin therapy to maintain a TSH between 0.3 and two for the remainder of pregnancy. However, we are lacking data supporting any effect on this, on prognosis. Finally, if the patient has significant growth of the cancer or nodal metastasis or locally advanced disease, surgery is recommended preferably in the second trimester. I would like to note also that radioactive iodine is contraindicated in pregnancy and the safety of tyrosine kinase inhibitors is actually uncertain. To conclude, appropriate diagnosis and treatment of hypothyroidism and hyperthyroidism in pregnancy is necessary to prevent poor maternal and fetal outcomes. Levofloxacin therapy is a treatment of choice for hypothyroidism, particularly for overt hypothyroidism and for subclinical hypothyroidism, especially if TSH is more than four. Added thyroid drug therapy in pregnant women has a lot of unknowns and we can try to avoid it if possible. Pregnancies at risk for fetal and neonatal hypothyroidism should and could be identified with drug measurements. Thyroid ultrasound and FNA are important diagnostic tools for thyroid nodules in pregnancy and the timing of surgery for pregnant women with differentiated thyroid cancer does not affect survival. Thank you so much for your attention and I'll be happy to take questions. Thank you, Dr. Moraka for such a comprehensive talk. We will now go ahead and open up the floor for Q&A. If you have not done so already, please type your question into the chat box. Time permitting, we will do our best to try to address each question. Dr. Moraka, the first question that is coming from the audience that I'd like to ask is, since it is a strong recommendation based on good quality evidence to have 150 micrograms of iodine per day in pregnancy, what can be done to make iodine a more uniform component of prenatal vitamins? That's a great question. I think it would help if we have the support from all the professional organizations to advocate about this. Obviously, we cannot force it, but there has been some positive development in this aspect. About 10 years ago, actually, there was a study that showed that among over 200 type multivitamins for pregnancy, there was not any iodine in there. There was some development where the industry started advocating that prenatal vitamins should have at least 150 micrograms of iodine in there. Whether this has been universally implemented, we don't yet know. But I would say increasing awareness and asking for support from our different organizations, either from endocrine or even from pediatrics, that would help towards that end. Thank you. The next question is, would you treat a normal TSH but a positive anti-TPO antibody level in pregnancy? That's a question that has raised a lot of debate. In the last guidelines from the American Heart Association, there is a weak recommendation about giving a small dose of levothyroxine in TPO euthyroid pregnant women who had a history of miscarriage. There's also the other recommendation that basically if the SH is between 2.5 and 4, and the antibody is positive, again, a weak recommendation where you could consider levothyroxine. That being said, we have more recent clinical trials that haven't showed any effectiveness of levothyroxine in this population where they're euthyroid with positive TPO antibodies. One of them is the POSTAL trial, where there were women who are euthyroid with positive TPO antibodies undergoing IVF were adonized to levothyroxine or placebo, and there was similar pregnancy rates and live birth between groups. We also have the TABLET trial, again, didn't show any effectiveness of levothyroxine in euthyroid TPO antibody-positive women. So with that in mind, and also having in mind that there is a possibility of overtreatment with levothyroxine that could have some adverse effects, I would be very skeptical to initiate levothyroxine treatment in a euthyroid woman. Of course, it has to go case by case, and I look forward to the updated guidelines that would take into account these new developments. Thank you. The next question I think gets into the matter of diagnostic versus treatment thresholds, and it is why is the TSH goal 2.5 for treatment when less than 4 seems okay? Okay, so as you kind of pointed out, there's a difference between a diagnostic TSH threshold and a treatment TSH threshold. So for diagnostic purposes, as you already mentioned, a TSH of 4 and above would indicate probably some type of dysfunction. Now, if treatment is started, we typically aim for a TSH of less than 2.5, again, borrowing data from the patients who have a history of overt hypothyroidism already on levothyroxine replacement. And as I showed in the presentation, we know that women who have a TSH, who were already on treatment, and they have a TSH more than 2.5, and that was not addressed, actually have a higher risk of miscarriage compared to pregnant women where the levothyroxine was increased in response to this elevated TSH level. So I would say we have this indirect data to dictate our treatment goals. Thank you. Why is TSH receptor antibody measurement not required in the group who is in remission following treatment with antithyroid medication, but it is recommended to be measured in the group that had been treated with radioactive iodine? Excellent. Excellent question. Well, the point here is that the TSH antibodies can close the placenta and stimulate the thyroid of the fetus that can increase the risk for developing fetal or neonatal hyperthyroidism. So in a woman who had received radioactive iodine in the past and now their euthyroid as a result of the treatment, they might still have a trabody body circulating, but they don't have thyroid to manifest itself. So their offspring is still at risk for hyperthyroidism. Now, if a woman is actually under remission, she has, because of antithyroid drug therapy, she still has a thyroid. So presumably if the trabody body level is high, she wouldn't be in remission. She would probably be hyperthyroid. And I think that's where this guideline is coming from. Thank you. That's all the time we have for today's session and for the Q&A. Thank you, Dr. Moraka, for the in-depth discussion. There are still some unanswered questions, but Dr. Moraka will have the ability at the end to try to answer some of these unanswered questions to the best of her ability. Thank you once again for the discussion. Thank you everybody for participating this afternoon and enjoy the rest of the conference. Thank you. Bye.

thyroid disease

pregnancy

thyroid physiology

hypothyroidism

levothyroxine

subclinical hypothyroidism

hyperthyroidism

thyroid nodules

thyroid cancer

maternal and fetal outcomes