Use of liothyronine (T3) in hypothyroidism: Joint British Thyroid Association/Society for endocrinology consensus statement.

Persistent symptoms in patients treated for hypothyroidism are common. Despite more than 20 years of debate, the use of liothyronine for this indication remains controversial, as numerous randomised trials have failed to show a benefit of treatment regimens that combine liothyronine (T3) with levothyroxine over levothyroxine monotherapy. This consensus statement attempts to provide practical guidance to clinicians faced with patients who have persistent symptoms during thyroid hormone replacement therapy. It applies to non-pregnant adults and is focussed on care delivered within the UK National Health Service, although it may be relevant in other healthcare environments. The statement emphasises several key clinical practice points for patients dissatisfied with treatment for hypothyroidism. Firstly, it is important to establish a diagnosis of overt hypothyroidism; patients with persistent symptoms during thyroid hormone replacement but with no clear biochemical evidence of overt hypothyroidism should first have a trial without thyroid hormone replacement. In those with established overt hypothyroidism, levothyroxine doses should be optimised aiming for a TSH in the 0.3-2.0 mU/L range for 3 to 6 months before a therapeutic response can be assessed. In some patients, it may be acceptable to have serum TSH below reference range (e.g. 0.1-0.3 mU/L), but not fully suppressed in the long term. We suggest that for some patients with confirmed overt hypothyroidism and persistent symptoms who have had adequate treatment with levothyroxine and in whom other comorbidities have been excluded, a trial of liothyronine/levothyroxine combined therapy may be warranted. The decision to start treatment with liothyronine should be a shared decision between patient and clinician. However, individual clinicians should not feel obliged to start liothyronine or to continue liothyronine medication provided by other health care practitioners or accessed without medical advice, if they judge this not to be in the patient's best interest.

Postradioiodine Graves' management: The PRAGMA study.

OBJECTIVE: Thyroid status in the months following radioiodine (RI) treatment for Graves' disease can be unstable. Our objective was to quantify frequency of abnormal thyroid function post-RI and compare effectiveness of common management strategies. DESIGN: Retrospective, multicentre and observational study. PATIENTS: Adult patients with Graves' disease treated with RI with 12 months' follow-up. MEASUREMENTS: Euthyroidism was defined as both serum thyrotropin (thyroid-stimulating hormone [TSH]) and free thyroxine (FT4) within their reference ranges or, when only one was available, it was within its reference range; hypothyroidism as TSH ≥ 10 mU/L, or subnormal FT4 regardless of TSH; hyperthyroidism as TSH below and FT4 above their reference ranges; dysthyroidism as the sum of hypo- and hyperthyroidism; subclinical hypothyroidism as normal FT4 and TSH between the upper limit of normal and <10 mU/L; and subclinical hyperthyroidism as low TSH and normal FT4. RESULTS: Of 812 patients studied post-RI, hypothyroidism occurred in 80.7% and hyperthyroidism in 48.6% of patients. Three principal post-RI management strategies were employed: (a) antithyroid drugs alone, (b) levothyroxine alone, and (c) combination of the two. Differences among these were small. Adherence to national guidelines regarding monitoring thyroid function in the first 6 months was low (21.4%-28.7%). No negative outcomes (new-onset/exacerbation of Graves' orbitopathy, weight gain, and cardiovascular events) were associated with dysthyroidism. There were significant differences in demographics, clinical practice, and thyroid status postradioiodine between centres. CONCLUSIONS: Dysthyroidism in the 12 months post-RI was common. Differences between post-RI strategies were small, suggesting these interventions alone are unlikely to address the high frequency of dysthyroidism.

Patient-led rapid titration of basal insulin in gestational diabetes is associated with improved glycaemic control and lower birthweight.

AIMS: Elevated fasting blood glucose in gestational diabetes (GDM) is a key predictor of high birthweight babies and adverse pregnancy outcomes but is hard to treat. We implemented a simple, patient-led, insulin dose titration algorithm aiming to improve fasting glycaemic control in GDM. METHODS: In women with GDM, initiating basal insulin, we recommended a daily four-unit dose increase after every fasting glucose value ≥5.0 mmol/mol (90 mg/dl). This approach augmented our pre-existing intensive (weekly) specialist nursing input. Using a before-and-after retrospective observational study design, we examined insulin doses and glucose values at 36 weeks gestation and maternal and neonatal outcomes in 105 women completing pregnancy before and 93 women after the intervention. RESULTS: The baseline characteristics of women in the before and after groups were the same. Women initiated on insulin after implementation (n = 30 before, n = 43 after) achieved substantially higher doses at 36 weeks (53 vs. 36 units/day; 0.56 vs. 0.37 units/kg/day; p = 0.027). 36-week mean fasting glucose was lower in those on insulin after implementation (4.6 vs. 5.1 mmol/L [83 vs. 92 mg/dl]; p = 0.031). Birthweight was significantly reduced (birthweight Z-scores 0.34 vs. 0.92; p = 0.005). There was no significant difference in macrosomia (after; 2% vs. before; 17% p = 0.078) or caesarean sections (after; 33% vs. before; 47%; p = 0.116). No women experienced severe hypoglycaemia. There were no outcome differences before versus after intervention in women not treated with insulin. CONCLUSIONS: Patient-led daily insulin titration in gestational diabetes leads to higher insulin dose use lower fasting glucose and is associated with lower birthweight without causing significant hypoglycaemia.

Diagnostic RET genetic testing in 1,058 index patients: A UK centre perspective.

OBJECTIVE: Diagnostic germline RET analysis is offered to all patients with a diagnosis of medullary thyroid carcinoma (MTC), or other conditions associated with multiple endocrine neoplasia type 2 (MEN2) in the United Kingdom. Here, we report the experience of a single centre's germline RET analysis over a 21-year period. DESIGN: Retrospective case-note review. PATIENTS: All index patients referred to the Exeter Genomics Laboratory for diagnostic germline RET analysis between 1997 and 2018, and unaffected family members, undergoing predictive testing. MEASUREMENTS: The rate and nature of pathogenic variant detection were recorded, as well as the indication for testing. RESULTS: 1,058 index patients and 551 unaffected family members were tested. The overall rate of pathogenic variant detection was 10.2% amongst index patients and 29% amongst unaffected family members. The commonest indication was isolated MTC, and amongst the 690 patients with isolated MTC, 68 (9.9%) were found to harbour a RET pathogenic variant. Of those with presumed sporadic MTC, 8.5% were found to harbour germline RET pathogenic variants, compared with 36.4% of those with a family history of MEN2-associated conditions. Pathogenic variants were identified in 3.6% and 0% of patients with isolated phaeochromocytoma and primary hyperparathyroidism, respectively. CONCLUSIONS: Although the detection rate of RET germline pathogenic variants in patients with presumed sporadic MTC was significant, the overall detection rate in those with MTC was lower than expected in this series. Advances in RET analysis in response to reports of new variants over the last two decades are likely to have improved the pick-up rate in recent years.

The role of molecular genetics in the clinical management of sporadic medullary thyroid carcinoma: A systematic review.

BACKGROUND: The significant variation in the clinical behaviour of sporadic medullary thyroid carcinoma (sMTC) causes uncertainty when planning the management of these patients. Several tumour genetic and epigenetic markers have been described, but their clinical usefulness remains unclear. The aim of this review was to evaluate the evidence for the use of molecular genetic and epigenetic profiles in the risk stratification and management of sMTC. METHODS: MEDLINE and Embase databases were searched using the MeSH terms "medullary carcinoma", "epigenetics", "molecular genetics", "microRNAs"; and free text terms "medullary carcinoma", "sporadic medullary thyroid cancer", "sMTC", "RET", "RAS" and "miR". Articles containing less than ten subjects, not focussing on sMTC, or not reporting clinical outcomes were excluded. Risk of bias was assessed using a modified version of the Newcastle-Ottawa Scale. RESULTS: Twenty-three studies met the inclusion criteria, and key findings were summarized in themes according to the genetic and epigenetic markers studied. There is good evidence that somatic RET mutations predict higher rates of lymph node metastasis and persistent disease, and worse survival. There are also several good quality studies demonstrating associations between certain epigenetic markers such as tumour miR-183 and miR-375 expression and higher rates of lymph node and distant metastasis, and worse survival. CONCLUSIONS: There is a growing body of evidence that tumour genetic and epigenetic profiles can be used to risk stratify patients with sMTC. Further research should focus on the clinical applicability of these findings by investigating the possibility of tailoring management to an individual's tumour mutation profile.

Utility of systematic TSHR gene testing in adults with hyperthyroidism lacking overt autoimmunity and diffuse uptake on thyroid scintigraphy.

OBJECTIVE: Patients with hyperthyroidism lacking autoimmune features but showing diffuse uptake on thyroid scintigram can have either Graves' disease or germline activating TSH receptor (TSHR) mutation. It is important to identify patients with activating TSHR mutation due to treatment implication, but the overlapping clinical features with Graves' disease make it difficult to discriminate these two conditions without genetic testing. Our study aimed to assess the potential of systematic TSHR mutation screening in adults with hyperthyroidism, showing diffuse uptake on thyroid scintigraphy but absence of TSH receptor antibodies (TRAb) and clinical signs of autoimmunity. DESIGN: A cross-sectional study of Caucasian adults with hyperthyroidism, managed at three endocrine centres in the South West, UK, from January 2006 to April 2017. METHODS: We recruited 78 adult Caucasian patients with hyperthyroidism showing diffuse uptake on 99m Tc-pertechnetate thyroid scintigraphy but without TRAb and other autoimmune clinical features of Graves' disease (such as thyroid-associated ophthalmopathy or dermopathy). Genomic DNA of these patients was analysed for variants in the TSHR gene. RESULTS: Genetic analysis identified 11 patients with four variants in TSHR [p.(Glu34Lys), p.(Asp36His), p.(Pro52Thr) and p.(Ile334Thr)]. None of these variants were pathogenic according to the American College of Medical Genetics and Genomics guideline. CONCLUSIONS: Activating TSHR mutations are a rare cause of nonautoimmune adult hyperthyroidism. Our study does not support the routine genetic testing in adult patients with hyperthyroidism showing diffuse uptake on scintigraphy but negative TRAb and lacking extrathyroidal manifestations of Graves' disease.

Association of Thyroid Function Test Abnormalities and Thyroid Autoimmunity With Preterm Birth: A Systematic Review and Meta-analysis.

Importance: Maternal hypothyroidism and hyperthyroidism are risk factors for preterm birth. Milder thyroid function test abnormalities and thyroid autoimmunity are more prevalent, but it remains controversial if these are associated with preterm birth. Objective: To study if maternal thyroid function test abnormalities and thyroid autoimmunity are risk factors for preterm birth. Data Sources and Study Selection: Studies were identified through a search of the Ovid MEDLINE, EMBASE, Web of Science, the Cochrane Central Register of Controlled Trials, and Google Scholar databases from inception to March 18, 2018, and by publishing open invitations in relevant journals. Data sets from published and unpublished prospective cohort studies with data on thyroid function tests (thyrotropin [often referred to as thyroid-stimulating hormone or TSH] and free thyroxine [FT4] concentrations) or thyroid peroxidase (TPO) antibody measurements and gestational age at birth were screened for eligibility by 2 independent reviewers. Studies in which participants received treatment based on abnormal thyroid function tests were excluded. Data Extraction and Synthesis: The primary authors provided individual participant data that were analyzed using mixed-effects models. Main Outcomes and Measures: The primary outcome was preterm birth (<37 weeks' gestational age). Results: From 2526 published reports, 35 cohorts were invited to participate. After the addition of 5 unpublished data sets, a total of 19 cohorts were included. The study population included 47 045 pregnant women (mean age, 29 years; median gestational age at blood sampling, 12.9 weeks), of whom 1234 (3.1%) had subclinical hypothyroidism (increased thyrotropin concentration with normal FT4 concentration), 904 (2.2%) had isolated hypothyroxinemia (decreased FT4 concentration with normal thyrotropin concentration), and 3043 (7.5%) were TPO antibody positive; 2357 (5.0%) had a preterm birth. The risk of preterm birth was higher for women with subclinical hypothyroidism than euthyroid women (6.1% vs 5.0%, respectively; absolute risk difference, 1.4% [95% CI, 0%-3.2%]; odds ratio [OR], 1.29 [95% CI, 1.01-1.64]). Among women with isolated hypothyroxinemia, the risk of preterm birth was 7.1% vs 5.0% in euthyroid women (absolute risk difference, 2.3% [95% CI, 0.6%-4.5%]; OR, 1.46 [95% CI, 1.12-1.90]). In continuous analyses, each 1-SD higher maternal thyrotropin concentration was associated with a higher risk of preterm birth (absolute risk difference, 0.2% [95% CI, 0%-0.4%] per 1 SD; OR, 1.04 [95% CI, 1.00-1.09] per 1 SD). Thyroid peroxidase antibody-positive women had a higher risk of preterm birth vs TPO antibody-negative women (6.6% vs 4.9%, respectively; absolute risk difference, 1.6% [95% CI, 0.7%-2.8%]; OR, 1.33 [95% CI, 1.15-1.56]). Conclusions and Relevance: Among pregnant women without overt thyroid disease, subclinical hypothyroidism, isolated hypothyroxinemia, and TPO antibody positivity were significantly associated with higher risk of preterm birth. These results provide insights toward optimizing clinical decision-making strategies that should consider the potential harms and benefits of screening programs and levothyroxine treatment during pregnancy.

Maternal thyroid hormone insufficiency during pregnancy and risk of neurodevelopmental disorders in offspring: A systematic review and meta-analysis.

BACKGROUND: In the last 2 decades, several studies have examined the association between maternal thyroid hormone insufficiency during pregnancy and neurodevelopmental disorders in children and shown conflicting results. AIM: This systematic review aimed to assess the evidence for an association between maternal thyroid hormone insufficiency during pregnancy and neurodevelopmental disorders in children. We also sought to assess whether levothyroxine treatment for maternal thyroid hormone insufficiency improves child neurodevelopment outcomes. METHODS: We performed systematic literature searches in MEDLINE, EMBASE, PSYCinfo, CINAHL, AMED, BNI, Cochrane, Scopus, Web of Science, GreyLit, Grey Source and Open Grey (latest search: March 2017). We also conducted targeted web searching and performed forwards and backwards citation chasing. Meta-analyses of eligible studies were carried out using the random-effects model. RESULTS: We identified 39 eligible articles (37 observational studies and 2 randomized controlled trials [RCT]). Meta-analysis showed that maternal subclinical hypothyroidism and hypothyroxinaemia are associated with indicators of intellectual disability in offspring (odds ratio [OR] 2.14, 95% confidence interval [CI] 1.20 to 3.83, P = .01, and OR 1.63, 95% CI 1.03 to 2.56, P = .04, respectively). Maternal subclinical hypothyroidism and hypothyroxinaemia were not associated with attention deficit hyperactivity disorder, and their effect on the risk of autism in offspring was unclear. Meta-analysis of RCTs showed no evidence that levothyroxine treatment for maternal hypothyroxinaemia or subclinical hypothyroidism reduces the incidence of low intelligence quotient in offspring. LIMITATIONS: Although studies were generally of good quality, there was evidence of heterogeneity between the included observational studies (I2 72%-79%). CONCLUSION: Maternal hypothyroxinaemia and subclinical hypothyroidism may be associated with intellectual disability in offspring. Currently, there is no evidence that levothyroxine treatment, when initiated 8- to 20-week gestation (mostly between 12 and 17 weeks), for mild maternal thyroid hormone insufficiency during pregnancy reduces intellectual disability in offspring.

Changing trend in referral to secondary care specialist thyroid eye disease clinic following the Amsterdam declaration.

INTRODUCTION: Early diagnosis and treatment of thyroid eye disease (TED) improves outcomes. Previous studies have highlighted delays in diagnosis and referral to specialist centres. The Amsterdam declaration (2009) aimed to halve the time from presentation to diagnosis and from diagnosis to referral to a specialist centre in five years. A recent study from the European group on Graves' orbitopathy tertiary centres showed a trend for earlier referral of patients to the centres. It is unknown whether similar improvements are occurring in secondary care hospitals in the UK. AIM: To study the trend in referral to a UK secondary care specialist TED clinic since the Amsterdam declaration. METHODS: We carried out a prospective audit of patients who attended the specialist TED clinic after the Amsterdam declaration (2010-2015). We compared their clinical characteristics, including duration of symptoms, disease activity and severity, with those of the patients (n = 114) from an earlier audit attending the clinic during 2004-2008. RESULTS: During 2010-2015, 126 patients with TED (97 females, median age 55 years, 39 current smokers) attended the clinic. The median time from onset of symptoms to being seen in the clinic was 5 months, reduced from 12 months in 2004-2008 (p < 0.001). As compared to the 2004-2008 cohort, significantly more patients in the current cohort presented with mild disease (72 vs. 52%, p = 0.002). Twenty-seven per cent patients had active TED (clinical activity score ≥3/7) compared to 18% in 2004-2008 (p = 0.1). CONCLUSIONS: The trend in referral to secondary care specialist TED clinic is changing in line with the Amsterdam declaration aims.

Raising awareness of Graves' orbitopathy with early warning cards.

BACKGROUND: Clinically significant Graves' orbitopathy (GO) develops in about 25% of those with Graves' disease (GD); most cases of GD in the UK are managed by endocrinologists. Despite this, patients report significant delays before a diagnosis of GO is made. Measures to increase awareness of the early signs of GO and establishing a fast-track referral pathway to specialist care should overcome these delays and potentially improve outcomes. AIMS: We aimed to determine whether issuing a "GO early warning card" to all GD patients raises awareness of GO and facilitates early diagnosis, what percentage of cards result in a telephone contact, the number of "false reports" from card carriers and patient perceptions of the cards. METHODS: We designed cards, detailing common GO symptoms and a telephone number for patients developing symptoms. Cards were distributed to 160 GD patients, without known GO, attending four endocrine clinics in the UK (December 2015-March 2016). We recorded telephone contacts over twelve months from when the last card was distributed and gathered patient feedback. RESULTS: The early warning cards were well received by patients in general. Over twelve months, ten telephone contacts from nine patients, all related to ocular symptoms, were received (6% of cards issued). Nine calls resulted in an additional clinic review (for eight patients), and four diagnoses of GO were made. CONCLUSIONS: This pilot study demonstrates that it is feasible to distribute GO early warning cards in clinic, and that they can be used to facilitate an early diagnosis of GO.

Iodine deficiency amongst pregnant women in South-West England.

INTRODUCTION: Iodine deficiency in pregnancy may impair foetal neurological development. The UK population is generally thought to be iodine sufficient; however, recent studies have questioned this assumption. Our study aimed to explore the prevalence of iodine deficiency in a cohort of pregnant mothers from South-West England. METHODS: Urine samples were obtained from 308 women participating in a study of breech presentation in late pregnancy. They had no known thyroid disease and a singleton pregnancy at 36-38 weeks' gestation. Samples were analysed for urinary iodine concentrations (UIC). Baseline data included age, parity, smoking status, ethnicity, body mass index (BMI) at booking, prenatal vitamin use and a dietary questionnaire. There was no difference in median UIC between women with (n = 156) or without (n = 152) a breech presentation (P = 0·3), so subsequent analyses were carried out as a combined group. RESULTS: Participants had a mean (SD) age 31(5) years, median (IQR) BMI 24·4 (22·0, 28·3) kg/m2 ; 42% were primiparous, 10% smoked during pregnancy, and 35% took iodine-containing vitamins. Ninety-six per cent were Caucasian. Median (IQR) UIC was 88·0 (54·3, 157·5) µg/l, which is consistent with iodine deficiency by WHO criteria. A total of 224/308 (73%) of women had UIC values <150 µg/l. Increasing milk intake was associated with higher UIC (P = 0·02). There was no difference in median (IQR) UIC between those women who took iodine-containing vitamins (n = 108) and those who did not (n = 200): 88 (54, 168) vs 88 (54, 150) µg/l, P = 0·7. CONCLUSION: Iodine deficiency in pregnancy is common in South-West England. Measures to develop optimum prevention and treatment strategies are urgently needed.

SOS1 frameshift mutations cause pure mucosal neuroma syndrome, a clinical phenotype distinct from multiple endocrine neoplasia type 2B.

BACKGROUND: Mucosal neuromas, thickened corneal nerves and marfanoid body habitus are characteristic phenotypic features of multiple endocrine neoplasia type 2B (MEN2B) and often provide an early clue to the diagnosis of the syndrome. Rarely, patients present with typical physical features of MEN2B but without associated endocrinopathies (medullary thyroid carcinoma or pheochromocytoma) or a RET gene mutation; this clinical presentation is thought to represent a distinct condition termed 'pure mucosal neuroma syndrome'. METHODS: Exome sequencing was performed in two unrelated probands with mucosal neuromas, thickened corneal nerves and marfanoid body habitus, but no MEN2B-associated endocrinopathy or RET gene mutation. Sanger sequencing was performed to confirm mutations detected by exome sequencing and to test in family members and 3 additional unrelated index patients with mucosal neuromas or thickened corneal nerves. RESULTS: A heterozygous SOS1 gene frameshift mutation (c.3266dup or c.3248dup) was identified in each proband. Sanger sequencing showed that proband 1 inherited the c.3266dup mutation from his affected mother, while the c.3248dup mutation had arisen de novo in proband 2. Sanger sequencing also identified one further novel SOS1 mutation (c.3254dup) in one of the 3 additional index patients. CONCLUSION: Our results demonstrate the existence of pure mucosal neuroma syndrome as a clinical entity distinct from MEN2B that can now be diagnosed by genetic testing.

Management of patients with Graves' orbitopathy: initial assessment, management outside specialised centres and referral pathways.

Graves' orbitopathy (GO) is uncommon, but responsible for considerable morbidity. A coordinated approach between healthcare professionals is required in order to meet the needs of patients. Early diagnosis can be achieved by a simple clinical assessment. Low-cost effective interventions can be initiated by generalists, which may improve outcomes. Moderate-to-severe GO should be referred to specialised centres. Recommendations for clinical diagnosis, initial management and referral pathways are highlighted.

Block & replace regime versus titration regime of antithyroid drugs for the treatment of Graves' disease: a retrospective observational study.

CONTEXT: Two widely used antithyroid drug (ATD) regimes for Graves' disease (GD) include the 'block & replace' (B&R) regime (a fixed high-dose of ATD combined with levothyroxine) and the 'titration' regime (a titrating dose of ATD). Anecdotally, it is believed that B&R is less prone to fluctuating thyroid function. OBJECTIVE: To study whether, in routine clinical practice, the B&R regime, compared with the titration regime, is associated with more stable thyroid function. METHODS: We retrospectively analysed case-records for 450 patients treated with ATDs for GD at a secondary care hospital. Exclusion criteria included treatment with ATDs for <6 months, thyrotoxicosis due to other causes, treatment with radioiodine or thyroidectomy and pregnancy. RESULTS: Two hundred and twenty three patients were treated with the B&R regime ('B&R group'), 149 with the titration regime ('titration group') and 78 with both regimes. The number of thyroid function tests (TFTs) performed per year (mean(SD): 3·2(1·2) vs 3·4(1·5); adjusted mean difference = -0·4; 95% CI: -0·7 to -0·1; and P = 0·008) and the number of hospital clinic visits per year (mean (SD): 2·9 (1·0) vs 3·2 (1·3); adjusted mean difference = -0·4; 95% CI: -0·7 to -0·2; and P = 0·002) were lower in the B&R group than the titration group. The number of abnormal TFT results per year was similar in the two groups (mean(SD): 1·8(1·3) vs 1·8(1·4); adjusted mean difference = 0·05; 95%CI: -0·3 to 0·4; and P = 0·74). CONCLUSIONS: In this retrospective study, there was little evidence that patients under B&R have more stable thyroid function. Further data from prospective studies, however, are needed to confirm this finding.

Screening and management of hypothyroidism in pregnancy: results of an Asian survey.

Maternal hypothyroidism in pregnancy is associated with several adverse outcomes. The American Thyroid Association and the Endocrine Society Guidelines for the management of thyroid diseases in pregnancy were published in 2011 and 2012, respectively; however, impact of the guidelines in routine clinical practice is unknown. We therefore carried out a survey to study current practices in the screening and management of hypothyroidism in pregnancy. We collected completed questionnaire survey based on clinical case scenarios from 321 members of the Asia-Oceania Thyrpid Association (AOTA). Responses from 310 clinician members (from 21 Asian countries) were analyzed. For a woman with hypothyroidism planning pregnancy, 54% favored testing thyroid function before adjusting the dose, whilst 32% recommended increasing the dose of L-thyroxine (L-T4) as soon as pregnancy is confirmed. For a pregnant woman with newly diagnosed overt hypothyroidism, most responders initiated a full dose of L-T4. One half of responders used serum TSH and free T4 to monitor the dose of L-T4. Although the target of thyroid function tests that responders aimed to achieve with L-T4 was inconsistent, but a majority aim to keep TSH within recommended trimester specific range. Twenty-one % responders or their institutions screened all pregnant women for thyroid dysfunction, 66% performed targeted screening of only the high-risk group, whilst 13% did not carry out systemic screening. Majority of responders practices within recommendations of major professional societies; however, there is wide variation in the clinical practice in the treatment and screening of hypothyroidism during pregnancy in Asia.

Management of hyperthyroidism during pregnancy in Asia.

Maternal hyperthyroidism in pregnancy is associated with adverse impacts on both mother and fetus. Recently, the American Thyroid Association and the Endocrine Society have published guidelines for the management of thyroid diseases in pregnancy. We aimed to disclose the impact of these guidelines in current practices of Asian members of the Asia-Oceania Thyroid Association (AOTA) regarding the management of hyperthyroidism in pregnancy. Completed questionnaire survey, based on clinical case scenarios, was collected from 321 Asian physician members of AOTA from 21 Asian countries in 2013. For a woman with Graves' disease planning pregnancy, 92% of clinicians favored antithyroid treatment, 52% with propylthiouracil (PTU) while 40% preferred methimazole (MMI). For a pregnant woman with newly diagnosed overt hyperthyroidism, nearly all responders initiated PTU treatment. To monitor dosage of antithyroid drugs, approximately 73% of responders used TSH and free T4 (FT4) levels without free T3 (FT3) (53%) or with FT3 (20%). Majority of responders targeted achieving low serum TSH with FT4 (or total T4) in the upper end of the normal range. For management of gestational thyrotoxicosis, 40% chose to follow up and 52% treated patients with PTU. Although timing of TSH receptor antibodies measurement in pregnant hyperthyroid patients was variable, 53% of responders would check it at least once during pregnancy. Nearly 80% of responders do not treat subclinical hyperthyroidism in pregnancy. Therefore, despite wide variations in the management of hyperthyroidism during pregnancy in Asia, majority of Asian physicians practice within the recommendations of major professional societies.

Exploring reasons for variation in ordering thyroid function tests in primary care: a qualitative study.

BACKGROUND: The ordering of thyroid function tests (TFTs) is increasing but there is not a similar increase in thyroid disorders in the general population, leading some to query whether inappropriate testing is taking place. Inconsistent clinical practice is thought to be a cause of this, but there is little evidence of the views of general practitioners, practice nurses or practice managers on the reasons for variation in the ordering of TFTs. AIM: To find out the reasons for variation in ordering of TFTs from the perspective of primary healthcare professionals Methods: Fifteen semi-structured interviews were carried out with primary healthcare professionals (general practitioners, practice nurses, practice managers) that used one laboratory of a general hospital in South West England for TFTs. Framework Analysis was used to analyse views on test ordering variation at the societal, practice, individual practitioner and patient level. RESULTS: A number of reasons for variation in ordering across practices were suggested. These related to: primary healthcare professionals awareness of and adherence to national policy changes; practices having different protocols on TFTs ordering; the set-up and use of computer systems in practices; the range of practice healthcare professionals able to order TFTs; greater risk-aversion amongst general practitioners and changes in their training and finally how primary healthcare staff responded to patients who were perceived to seek help more readily than in the past. CONCLUSION: The reasons for variation in TFTs ordering are complex and interdependent. Interventions to reduce variation in TFTs ordering need to consider multiple behavioural and contextual factors to be most effective.

TSH and FT4 Reference Interval Recommendations and Prevalence of Gestational Thyroid Dysfunction: Quantification of Current Diagnostic Approaches.

CONTEXT: Guidelines recommend use of population- and trimester-specific thyroid-stimulating hormone (TSH) and free thyroxine (FT4) reference intervals (RIs) in pregnancy. Since these are often unavailable, clinicians frequently rely on alternative diagnostic strategies. We sought to quantify the diagnostic consequences of current recommendations. METHODS: We included cohorts participating in the Consortium on Thyroid and Pregnancy. Different approaches were used to define RIs: a TSH fixed upper limit of 4.0 mU/L (fixed limit approach), a fixed subtraction from the upper limit for TSH of 0.5 mU/L (subtraction approach) and using nonpregnancy RIs. Outcome measures were sensitivity and false discovery rate (FDR) of women for whom levothyroxine treatment was indicated and those for whom treatment would be considered according to international guidelines. RESULTS: The study population comprised 52 496 participants from 18 cohorts. Compared with the use of trimester-specific RIs, alternative approaches had a low sensitivity (0.63-0.82) and high FDR (0.11-0.35) to detect women with a treatment indication or consideration. Sensitivity and FDR to detect a treatment indication in the first trimester were similar between the fixed limit, subtraction, and nonpregnancy approach (0.77-0.11 vs 0.74-0.16 vs 0.60-0.11). The diagnostic performance to detect overt hypothyroidism, isolated hypothyroxinemia, and (sub)clinical hyperthyroidism mainly varied between FT4 RI approaches, while the diagnostic performance to detect subclinical hypothyroidism varied between the applied TSH RI approaches. CONCLUSION: Alternative approaches to define RIs for TSH and FT4 in pregnancy result in considerable overdiagnosis and underdiagnosis compared with population- and trimester-specific RIs. Additional strategies need to be explored to optimize identification of thyroid dysfunction during pregnancy.

Presentation of Graves' orbitopathy within European Group On Graves' Orbitopathy (EUGOGO) centres from 2012 to 2019 (PREGO III).

BACKGROUND: Graves' orbitopathy (GO) is subject to epidemiological and care-related changes. Aim of the survey was to identify trends in presentation of GO to the European Group On Graves' Orbitopathy (EUGOGO) tertiary referral centres and initial management over time. METHODS: Prospective observational multicentre study. All new referrals with diagnosis of GO within September-December 2019 were included. Clinical and demographic characteristics, referral timelines and initial therapeutic decisions were recorded. Data were compared with a similar EUGOGO survey performed in 2012. RESULTS: Besides age (mean age: 50.5±13 years vs 47.7±14 years; p 0.007), demographic characteristics of 432 patients studied in 2019 were similar to those in 2012. In 2019, there was a decrease of severe cases (9.8% vs 14.9; p<0.001), but no significant change in proportion of active cases (41.3% vs 36.6%; p 0.217). After first diagnosis of GO, median referral time to an EUGOGO tertiary centre was shorter (2 (0-350) vs 6 (0-552) months; p<0.001) in 2019. At the time of first visit, more patients were already on antithyroid medications (80.2% vs 45.0%; p<0.001) or selenium (22.3% vs 3.0%; p<0.001). In 2019, the initial management plans for GO were similar to 2012, except for lid surgery (2.4% vs 13.9%; p<0.001) and prescription of selenium (28.5% vs 21.0%; p 0.027). CONCLUSION: GO patients are referred to tertiary EUGOGO centres in a less severe stage of the disease than before. We speculate that this might be linked to a broader awareness of the disease and faster and adequate delivered treatment.

Association of Gestational Free and Total Triiodothyronine With Gestational Hypertension, Preeclampsia, Preterm Birth, and Birth Weight: An Individual Participant Data Meta-analysis.

CONTEXT: Triiodothyronine (T3) is the bioactive form of thyroid hormone. In contrast to thyroid-stimulating hormone and free thyroxine, we lack knowledge on the association of gestational T3 with adverse obstetric outcomes. OBJECTIVE: To investigate the associaiton of gestational free or total T3 (FT3 or TT3) with adverse obstetric outcomes. METHODS: We collected individual participant data from prospective cohort studies on gestational FT3 or TT3, adverse obstetric outcomes (preeclampsia, gestational hypertension, preterm birth and very preterm birth, small for gestational age [SGA], and large for gestational age [LGA]), and potential confounders. We used mixed-effects regression models adjusting for potential confounders. RESULTS: The final study population comprised 33 118 mother-child pairs of which 27 331 had data on FT3 and 16 164 on TT3. There was a U-shaped association of FT3 with preeclampsia (P = .0069) and a J-shaped association with the risk of gestational hypertension (P = .029). Higher TT3 was associated with a higher risk of gestational hypertension (OR per SD of TT3 1.20, 95% CI 1.08 to 1.33; P = .0007). A lower TT3 but not FT3 was associated with a higher risk of very preterm birth (OR 0.72, 95% CI 0.55 to 0.94; P = .018). TT3 but not FT3 was positively associated with birth weight (mean difference per 1 SD increase in TT3 12.8, 95% CI 6.5 to 19.1 g, P < .0001) but there was no association with SGA or LGA. CONCLUSION: This study provides new insights on the association of gestational FT3 and TT3 with major adverse pregnancy outcomes that form the basis for future studies required to elucidate the effects of thyroid function on pregnancy outcomes. Based on the current study, routine FT3 or TT3 measurements for the assessment of thyroid function during pregnancy do not seem to be of added value in the risk assessment for adverse outcomes.