Graves' disease.

Graves' disease (GD) is an autoimmune disease that primarily affects the thyroid gland. It is the most common cause of hyperthyroidism and occurs at all ages but especially in women of reproductive age. Graves' hyperthyroidism is caused by autoantibodies to the thyroid-stimulating hormone receptor (TSHR) that act as agonists and induce excessive thyroid hormone secretion, releasing the thyroid gland from pituitary control. TSHR autoantibodies also underlie Graves' orbitopathy (GO) and pretibial myxoedema. Additionally, the pathophysiology of GO (and likely pretibial myxoedema) involves the synergism of insulin-like growth factor 1 receptor (IGF1R) with TSHR autoantibodies, causing retro-orbital tissue expansion and inflammation. Although the aetiology of GD remains unknown, evidence indicates a strong genetic component combined with random potential environmental insults in an immunologically susceptible individual. The treatment of GD has not changed substantially for many years and remains a choice between antithyroid drugs, radioiodine or surgery. However, antithyroid drug use can cause drug-induced embryopathy in pregnancy, radioiodine therapy can exacerbate GO and surgery can result in hypoparathyroidism or laryngeal nerve damage. Therefore, future studies should focus on improved drug management, and a number of important advances are on the horizon.

The Need for Dynamic Clinical Guidelines: A Systematic Review of New Research Published After Release of the 2017 ATA Guidelines on Thyroid Disease During Pregnancy and the Postpartum.

Background: The American Thyroid Association Guidelines on Thyroid Disease During Pregnancy and the Postpartum (ATA Guidelines) were published in 2017, with an update not expected for another 5 years. Since release of the 2017 ATA Guidelines, greater than 500 articles have been published in the field. Furthermore, there are presently 14 prospective, interventional trials in progress registered at Clinicaltrials.gov Static guidelines updated every 5-7 years fail to provide timely evidence-based guidance to practicing clinicians. Consequently, guideline development should move toward the creation of dynamic documents. The present article reviews the literature published since the 2017 ATA Guidelines, both to benefit clinicians in practice and to make the case for Dynamic ATA Guidelines. Methods: Using the search terms "thyroid" and "pregnancy," a systematic review of literature published in Pubmed from 3/1/2017 to 12/31/2018 was conducted. The titles and/or abstracts of all articles were reviewed. All articles were classified by subject headings used in the 2017 ATA Guidelines. English-text articles classified under "hypothyroidism" or "thyroid autoimmunity" were examined in full-text. Using the questions and recommendations put forth by the previous ATA Guidelines, relevant articles were selected for discussion in this review. Results: At the time of the search, 659 unique articles on "thyroid and pregnancy" were identified, including 66 original studies on hypothyroidism and 26 on thyroid autoimmunity. Of these, 26 studies on hypothyroidism and 18 studies on thyroid autoimmunity were selected for inclusion in this review based on specific questions in the 2017 ATA Guidelines. Based on these 44 articles, we propose two specific changes to the 2017 ATA Guidelines. Conclusion: Based on new research, we recommend the 2017 ATA Guidelines be updated to recommend against treating thyroid antibody-negative women diagnosed with subclinical hypothyroidism in the second trimester or later; to reflect new, moderate-quality evidence supporting the treatment of thyroid peroxidase antibody-negative women with elevated thyroid stimulating hormone levels in the first trimester or earlier; and to recommend against treatment of euthyroid, thyroid peroxidase antibody-positive women undergoing assisted reproductive technology. Transitioning to a Dynamic ATA Guidelines would allow for these and future recommendations to be implemented in real time.

Subclinical hypothyroidism and thyroid autoimmunity in recurrent pregnancy loss: a systematic review and meta-analysis.

OBJECTIVE: To determine whether overt/subclinical hypothyroidism and/or thyroid autoimmunity is associated with recurrent pregnancy loss (RPL) and whether treatment improves outcomes. DESIGN: Systematic review and meta-analysis. SETTING: University obstetrics and gynecology departments. PATIENT(S): Women with RPL and overt/subclinical hypothyroidism, and/or thyroid autoimmunity. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Associations between RPL and overt/subclinical hypothyroidism and/or thyroid autoimmunity and any effects of treatment. RESULT(S): After our review of articles from PubMed, EMBASE, Web of Science, and CENTRAL, we found two interventional studies in which levothyroxine did not improve the subsequent live-birth rate in women with subclinical hypothyroidism with or without thyroid antibodies. A meta-analysis of five studies revealed the prevalence of subclinical hypothyroidism in RPL to be 12.9% (95% confidence interval [CI], 0%-35.2%). A meta-analysis of 17 studies revealed a statistically significant association between RPL and thyroid autoimmunity (odds ratio 1.94; 95% CI, 1.43-2.64). However, a randomized study suggested that levothyroxine does not benefit euthyroid women with thyroid autoimmunity. CONCLUSION(S): Based on the limited observational studies available, no association exists between RPL and subclinical hypothyroidism, nor does levothyroxine improve subsequent pregnancy outcomes. An association exists between RPL and thyroid autoimmunity, but levothyroxine does not improve subsequent pregnancy outcomes. Women with RPL should be screened/treated for overt thyroid disease but not thyroid autoimmunity. Thyroid antibody screening is not supported by the published studies, and further randomized studies are needed. No recommendation regarding the treatment of subclinical hypothyroidism can be made at this time; prospective and randomized studies are urgently needed.

Universal screening for thyroid disease during pregnancy should be performed.

Thyroid disease can significantly impact the pregnant woman and her child. Human and animal studies have firmly linked overt hypothyroidism and overt hyperthyroidism to miscarriage, preterm delivery and other adverse pregnancy outcomes. Overt hypothyroidism and overt hyperthyroidism affect 1% of all pregnancies. Treatment is widely available, and if detected early, results in decreased rates of adverse outcomes. Universal screening for thyroid disease in pregnancy can identify patients with thyroid disease requiring treatment, and ultimately decrease rates of complications. Universal screening is cost-effective compared to the currently accepted practice of targeted screening and may even be cost-saving in some healthcare systems. Targeted screening, which is recommended by most professional associations, fails to detect a large proportion of pregnant women with thyroid disease. In fact, an increasing number of providers are performing universal screening for thyroid disease in pregnancy, contrary to society guidelines. Limited evidence concerning the impact of untreated and treated subclinical disease and thyroid autoimmunity has distracted from the core rationale for universal screening - the beneficial impact of detecting and treating overt thyroid disease. Evidence supporting universal screening for overt disease stands independently from that of subclinical and autoimmune disease. The time to initiate universal screening is now.

Differences in Diagnostic Criteria Mask the True Prevalence of Thyroid Disease in Pregnancy: A Systematic Review and Meta-Analysis.

BACKGROUND: The reported prevalence of thyroid disease in pregnancy varies widely through the published literature. These discrepancies are due to differences in criteria for euthyroidism, nationality, iodine status, and gestational age at screening. As a result, currently, an accepted rate of prevalence does not exist for the various thyroid diseases in pregnancy. Understanding the true prevalence rates of these disorders has important implications for clinical management and the ongoing discussion regarding universal screening. The aims of this study were to assess (i) the true prevalence of thyroid disorders in pregnancy and (ii) the impact of diagnostic methodology on these rates. METHODS: A systematic review was conducted of the existing literature, including the Pubmed database and references from relevant review articles. Sixty-three studies reporting prevalence of overt hypothyroidism, subclinical hypothyroidism, isolated hypothyroxinemia, subclinical hyperthyroidism, and overt hyperthyroidism in pregnant women were included. Studies were further classified by thyrotropin (TSH) cutoff for diagnosis in hypothyroid disease and timing of screening for hyperthyroid disease. Meta-analysis yielded pooled prevalence rates, with subgroup analyses for TSH cutoff and timing of screening. Analysis of studies using the 97.5th percentile TSH cutoff was assessed to yield the most accurate prevalence rates for hypothyroidism. RESULTS: Pooled prevalence rates for hypothyroidism calculated from studies using the 97.5th percentile as an upper limit for TSH were 0.50% for overt hypothyroidism, 3.47% for subclinical hypothyroidism, and 2.05% for isolated hypothyroxinemia. Pooled prevalence rates in the first and second trimesters for hyperthyroidism were 0.91% and 0.65%, respectively, for overt hyperthyroidism and 2.18% and 0.98%, respectively, for subclinical hyperthyroidism. CONCLUSION: Population-based, trimester-specific TSH cutoffs for diagnosis of hypothyroid disease in pregnancy result in more accurate diagnosis and better estimates for prevalence of disease. Prevalence of hyperthyroidism in pregnancy varies depending on timing of screening. The prevalence rates reported in this study represent the best estimate to date of the true rates of thyroid disease in pregnancy.

Iodine Content of the Best-Selling United States Adult and Prenatal Multivitamin Preparations.

BACKGROUND: Iodine is essential for thyroid hormone production and fetal development. Even mild maternal iodine deficiency in gestation may be associated with impaired child neurodevelopment. Iodine requirements increase during pregnancy and lactation. Supplements containing 150 µg/day are recommended by the American Thyroid Association for all U.S. women who are pregnant, lactating, or planning pregnancy. The contribution of multivitamin supplements as an iodine source for pregnant and nonpregnant US adults has not been well studied. This study aimed to understand better the contribution of the top-selling adult multivitamins (AMV) and prenatal multivitamins (PMV) to iodine nutrition in the United States. METHODS: Product names, dollar sales, unit and volume sales, and recommended daily intakes of the top-selling 99 AMV and 60 PMV from July 2016 to July 2017 were obtained from Information Resources, Inc. Iodine content and source were determined from product labels. After excluding private-label brands and unavailable product labels, a final sample of 89 AMV and 59 PMV was analyzed. RESULTS: Of the 89 AMV, 74.2% contained iodine. The median (range) iodine content of AMV was 150 µg (38-150 µg) per daily serving. Over the study period, 8,924,371,955 AMV doses were sold, of which 84.8% contained iodine. Thirty-four (57.6%) of the 59 PMV contained iodine, with a median (range) iodine content of 150 µg (25-290 µg) per daily serving. Over the study period, 466,927,559 PMV doses were sold, of which 76.8% contained iodine. All iodine-containing AMV used potassium iodine as an iodine source. Of iodine-containing PMV, 73.5% used potassium iodide, 23.5% kelp, and 2.9% inactivated Saccharomyces cerevisiae as an iodine source. CONCLUSIONS: During the one-year study period, a higher proportion of AMV doses than PMV doses contained iodine. Some PMV but no AMV included sources of iodine known to be highly variable. The median iodine content of the top-selling AMV and PMV was at the recommended 150 µg daily intake, but the range remains wide. Twenty-four percent of PMV doses sold did not contain iodine. More effort is needed to ensure adequate iodine content in prenatal vitamins for women who are pregnant, lactating, or planning pregnancy.

Implementing an Entrustable Professional Activities Framework in Undergraduate Medical Education: Early Lessons From the AAMC Core Entrustable Professional Activities for Entering Residency Pilot.

In 2014, the Association of American Medical Colleges (AAMC) published a list of 13 Core Entrustable Professional Activities for Entering Residency (Core EPAs) that medical school graduates might be expected to perform, without direct supervision, on the first day of residency. Soon after, the AAMC commissioned a five-year pilot with 10 medical schools across the United States, seeking to implement the Core EPA framework to improve the transition from undergraduate to graduate medical education.In this article, the pilot team presents the organizational structure and early results of collaborative efforts to provide guidance to other institutions planning to implement the Core EPA framework. They describe the aims, timeline, and organization of the pilot as well as findings to date regarding the concepts of entrustment, assessment, curriculum development, and faculty development. On the basis of their experiences over the first two years of the pilot, the authors offer a set of guiding principles for institutions intending to implement the Core EPA framework. They also discuss the impact of the pilot, its limitations, and next steps, as well as how the pilot team is engaging the broader medical education community. They encourage ongoing communication across institutions to capitalize on the expertise of educators to tackle challenges related to the implementation of this novel approach and to generate common national standards for entrustment. The Core EPA pilot aims to better prepare medical school graduates for their professional duties at the beginning of residency with the ultimate goal of improving patient care.

Impact of Levothyroxine in Miscarriage and Preterm Delivery Rates in First Trimester Thyroid Antibody-Positive Women With TSH Less Than 2.5 mIU/L.

BACKGROUND: Thyroid disease during pregnancy is associated with multiple adverse maternal and fetal outcomes. In particular, multiple observational studies have demonstrated an association between the presence of thyroid antibodies in euthyroid women in the first trimester of miscarriage and an increased rate of spontaneous miscarriage and preterm delivery. The present study is a prospective intervention trial of the effect of levothyroxine on the rate of miscarriage and preterm delivery in euthyroid thyroid-antibody positive women in the first trimester of pregnancy. METHODS: A total of 8530 women in the first trimester of pregnancy in Southern Italy were screened for TSH and thyroid antibodies. Group A consisted of 198 euthyroid thyroid antibody positive women treated with levothyroxine, group B consisted of 195 untreated euthyroid thyroid antibody positive women, and group C consisted of 197 untreated thyroid antibody negative women. RESULTS: The rate of miscarriage did not differ between the 3 groups (11.6%, 14.9%, and 8.1 %, P = .11). The rate of preterm delivery between the 3 groups was 6.9%, 10.8%, and 2.8% and was statistically significant (P = .01). The rate of preterm delivery was significantly different between groups B and C (P = .02) but was not significantly different between groups A and B (P = .27). CONCLUSIONS: In conclusion, the present study found that levothyroxine intervention had no impact on the rate of miscarriage and preterm delivery in euthyroid thyroid antibody positive women.

Postpartum Management of Women Begun on Levothyroxine during Pregnancy.

During pregnancy, the thyroid gland must produce 50% more thyroid hormone to maintain the euthyroid state. Women with decreased thyroid reserve preconception, most typically due to Hashimoto's thyroiditis, may develop hypothyroidism during pregnancy. Data over the last 20 years have reported a strong association between subclinical hypothyroidism and adverse maternal/fetal events. As a result of this association, an increasing number of women are being screened for thyroid disease either preconception or at the first prenatal visit. Consequently, an ever increasing number of women are being initiated on levothyroxine for the first time during pregnancy. At present, there are very limited guidelines related to the management of the thyroid disease in these women postpartum. Based on an understanding of the physiology of the thyroid gland during pregnancy and postpartum, and the personal clinical experience of the author, recommendations for the postpartum management of women who were started on levothyroxine during pregnancy are presented.

Marginal Iodine Status and High Rate of Subclinical Hypothyroidism in Washington DC Women Planning Conception.

INTRODUCTION: Subclinical hypothyroidism during pregnancy has been associated with adverse maternal and fetal outcomes. A subset of pregnant women in the United States have been shown to have mild iodine deficiency. No study has evaluated the thyroid and iodine status of women who are planning to become pregnant in the near future. METHODS: Thyroid function tests, thyroid antibodies, and urine iodine levels were evaluated in women presenting for preconception screening and counseling. A thyrotropin (TSH) level above 3.0 mIU/L was considered abnormal. RESULTS: One hundred and forty one women enrolled in the study. The median TSH level was 1.70 mIU/L (range 0.43-5.3 mIU/L). Sixteen women (11%) had a TSH above the upper limit of normal (>3.0 mIU/L). Eleven women (8%) were positive for TPO-Ab and 21 women (15%) for TgAb. Twenty-three women (16%) were positive for at least one thyroid antibody (TPOAb and/or TgAb). Median serum TSH concentrations were higher in women with detectable antithyroid antibodies than in women who were antibody negative (2.2 mIU/L vs. 1.7 mIU/L; p=0.005). The median urinary iodine concentration was 100.5 µg (range 19-843 µg/L). DISCUSSION: The present cohort exhibited the lowest median urinary iodine concentration levels to date reported in the United States for women in their childbearing years. One out of every nine women (11%) had thyroid function tests consistent with subclinical hypothyroidism.