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Context and Objectives: The Controlled Antenatal Thyroid Screening Study I (CATS-I) was a randomized controlled trial investigating the effects of levothyroxine therapy for suboptimal gestational thyroid function (SGTF), comparing outcomes in children of treated (SGTF-T) with untreated (SGTF-U) women during pregnancy. This follow-up study, CATS-II, reports the long-term effects on anthropometric, bone, and cardiometabolic outcomes in mothers and offspring and includes a group with normal gestational thyroid function (NGTF)., Design & Participants: 332 mothers (197 NGTF, 56 SGTF-U, 79 SGTF-T) aged 41.2±5.3 years (mean±SD) and 326 paired children assessed 9.3±1.0 years after birth for (i) body mass index (BMI); (ii) lean, fat, and bone mass by dual-energy X-ray absorptiometry; (iii) blood pressure, augmentation index, and aortic pulse-wave-velocity; and (iv) thyroid function, lipids, insulin, and adiponectin. The difference between group means was compared using linear regression., Results: Offspring's measurements were similar between groups. Although maternal BMI was similar between groups at CATS-I, after 9 years (at CATS-II) SGTF-U mothers showed higher BMI (median [interquartile ratio] 28.3 [24.6-32.6] kg/m2) compared with NGTF (25.8 [22.9-30.0] kg/m2; P = 0.029), driven by fat mass increase. At CATS-II SGTF-U mothers also had higher thyroid-stimulating hormone (TSH) values (2.45 [1.43-3.50] mU/L) than NGTF (1.54 [1.12-2.07] mU/L; P = 0.015), since 64% had never received levothyroxine. At CATS-II, SGTF-T mothers had BMI (25.8 [23.1-29.8] kg/m2, P = 0.672) and TSH (1.68 [0.89-2.96] mU/L; P = 0.474) values similar to NGTF mothers., Conclusions: Levothyroxine supplementation of women with SGTF did not affect long-term offspring anthropometric, bone, and cardiometabolic measurements. However, absence of treatment was associated with sustained long-term increase in BMI and fat mass in women with SGTF., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Adequate transplacental passage of maternal thyroid hormone is important for normal fetal growth and development. Maternal overt hypothyroidism and hyperthyroidism are associated with low birthweight, but important knowledge gaps remain regarding the effect of subclinical thyroid function test abnormalities on birthweight-both in general and during the late second and third trimester of pregnancy. The aim of this study was to examine associations of maternal thyroid function with birthweight., Methods: In this systematic review and individual-participant data meta-analysis, we searched MEDLINE (Ovid), Embase, Web of Science, the Cochrane Central Register of Controlled Trials, and Google Scholar from inception to Oct 15, 2019, for prospective cohort studies with data on maternal thyroid function during pregnancy and birthweight, and we issued open invitations to identify study authors to join the Consortium on Thyroid and Pregnancy. We excluded participants with multiple pregnancies, in-vitro fertilisation, pre-existing thyroid disease or thyroid medication usage, miscarriages, and stillbirths. The main outcomes assessed were small for gestational age (SGA) neonates, large for gestational age neonates, and newborn birthweight. We analysed individual-participant data using mixed-effects regression models adjusting for maternal age, BMI, ethnicity, smoking, parity, gestational age at blood sampling, fetal sex, and gestational age at birth. The study protocol was pre-registered at the International Prospective Register of Systematic Reviews, CRD42016043496., Findings: We identified 2526 published reports, from which 36 cohorts met the inclusion criteria. The study authors for 15 of these cohorts agreed to participate, and five more unpublished datasets were added, giving a study population of 48 145 mother-child pairs after exclusions, of whom 1275 (3·1%) had subclinical hypothyroidism (increased thyroid stimulating hormone [TSH] with normal free thyroxine [FT 4 ]) and 929 (2·2%) had isolated hypothyroxinaemia (decreased FT 4 with normal TSH). Maternal subclinical hypothyroidism was associated with a higher risk of SGA than was euthyroidism (11·8% vs 10·0%; adjusted risk difference 2·43%, 95% CI 0·43 to 4·81; odds ratio [OR] 1·24, 1·04 to 1·48; p=0·015) and lower mean birthweight (mean difference -38 g, -61 to -15; p=0·0015), with a higher effect estimate for measurement in the third trimester than in the first or second. Isolated hypothyroxinaemia was associated with a lower risk of SGA than was euthyroidism (7·3% vs 10·0%, adjusted risk difference -2·91, -4·49 to -0·88; OR 0·70, 0·55 to 0·91; p=0·0073) and higher mean birthweight (mean difference 45 g, 18 to 73; p=0·0012). Each 1 SD increase in maternal TSH concentration was associated with a 6 g lower birthweight (-10 to -2; p=0·0030), with higher effect estimates in women who were thyroid peroxidase antibody positive than for women who were negative (p interaction =0·10). Each 1 SD increase in FT 4 concentration was associated with a 21 g lower birthweight (-25 to -17; p<0·0001), with a higher effect estimate for measurement in the third trimester than the first or second., Interpretation: Maternal subclinical hypothyroidism in pregnancy is associated with a higher risk of SGA and lower birthweight, whereas isolated hypothyroxinaemia is associated with lower risk of SGA and higher birthweight. There was an inverse, dose-response association of maternal TSH and FT 4 (even within the normal range) with birthweight. These results advance our understanding of the complex relationships between maternal thyroid function and fetal outcomes, and they should prompt careful consideration of potential risks and benefits of levothyroxine therapy during pregnancy., Funding: Netherlands Organization for Scientific Research (grant 401.16.020)., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Context: Serum thyroid hormone levels differ between children and adults, but have not been studied longitudinally through childhood., Objective: To assess changes in thyroid-stimulating hormone (TSH) and thyroid hormone levels over childhood and their interrelationships., Design: Cohort study., Setting: The Avon Longitudinal Study of Parents and Children, a population-based birth cohort., Participants: A total of 4442 children who had thyroid function measured at age 7, and 1263 children who had thyroid function measured at age 15. Eight hundred eighty-four children had measurements at both ages., Main Outcome Measures: Reference ranges for TSH, free tri-iodothyronine (FT3), free thyroxine (FT4), their longitudinal stability, and interrelationships., Results: Children at age 7 years had a higher FT3 [6.17 pmol/L, standard deviation (SD) 0.62] than children at age 15 (5.83 pmol/L, SD 0.74); P < 0.0001 with 23.2% of children at age 7 having FT3 above the adult reference range. Higher FT3 levels at age 7 in boys (P = 0.0001) and girls (P = 0.04) were associated with attainment of a more advanced pubertal stage at age 13. TSH was positively associated with FT3 at age 7 and age 15 even after adjusting for confounders. In contrast, TSH was negatively associated with FT4., Conclusions: There are substantial changes in TSH and thyroid hormone levels over childhood, in particular for FT3, which appear to relate to pubertal readiness. Our data provide increased insight into the evolution of the pituitary-thyroid axis over childhood and may have implications for determining optimal ranges for thyroid hormone replacement in children., (Copyright © 2017 Endocrine Society)

Purpose of Review: The purpose of this study was to review several of the most recent and most important clinical studies regarding the effects of how genetic variation in the deiodinases can influence health., Recent Findings: Common variation in DIO1 but not DIO2 or DIO3 is robustly associated with thyroid hormone levels at genome-wide levels of significance although the effect is modest. There is growing evidence that common variation in DIO2, particularly the Thr92Ala substitution, is associated with important clinical endpoints including osteo-arthritis and intelligence quotient; however, the mechanism of action appears to vary between tissues with several unexpected pathways recently being elucidated including effects on Golgi function and DNA methylation. In addition, there is emerging evidence of interaction with iodine and thyroid status., Summary: The clinical importance of genetic variation in the deiodinases has yet to be fully elucidated and their impact is likely to vary between individuals and body systems dependent on multiple factors within tissues and coexistent diseases and environmental factors. Exploration of whether there are rare functional variants in the deiodinases is now possible in population studies, which may yield greater insight in the near future. Studies of the impact of genetic variation in the deiodinases in individuals with iodine deficiency, subclinical thyroid disease, or those on levothyroxine are urgently needed.

Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Here, for the heritable thyroid traits thyrotropin (TSH) and free thyroxine (FT4), we analyse whole-genome sequence data from the UK10K project (N=2,287). Using additional whole-genome sequence and deeply imputed data sets, we report meta-analysis results for common variants (MAF≥1%) associated with TSH and FT4 (N=16,335). For TSH, we identify a novel variant in SYN2 (MAF=23.5%, P=6.15 × 10(-9)) and a new independent variant in PDE8B (MAF=10.4%, P=5.94 × 10(-14)). For FT4, we report a low-frequency variant near B4GALT6/SLC25A52 (MAF=3.2%, P=1.27 × 10(-9)) tagging a rare TTR variant (MAF=0.4%, P=2.14 × 10(-11)). All common variants explain ≥20% of the variance in TSH and FT4. Analysis of rare variants (MAF<1%) using sequence kernel association testing reveals a novel association with FT4 in NRG1. Our results demonstrate that increased coverage in whole-genome sequence association studies identifies novel variants associated with thyroid function.

Objective: Thyroid dysfunction is associated with impaired cognitive development. Perchlorate decreases thyroidal iodine uptake, potentially reducing thyroid hormone production. It is unclear whether perchlorate exposure in early life affects neurodevelopment., Design: Historical cohort analysis., Patients: From 2002 to 2006, 21,846 women at gestational age <16 weeks recruited from antenatal clinics in Cardiff, UK and Turin, Italy were enrolled in the Controlled Antenatal Thyroid Screening Study (CATS). We undertook a retrospective analysis of 487 mother-child pairs in mothers who were hypothyroid/hypothyroxinemic during pregnancy and analyzed whether first trimester maternal perchlorate levels in the highest 10% of the study population were associated with increased odds of offspring IQ being in the lowest 10% at 3 years of age., Main Outcome Measures: Maternal urinary perchlorate, offspring IQ., Results: Urine perchlorate was detectable in all women (median 2.58 μg/L); iodine levels were low (median 72 μg/L). Maternal perchlorate levels in the highest 10% of the population increased the odds of offspring IQ being in the lowest 10% OR = 3.14 (95% CI 1.38, 7.13) P = .006 with a greater negative impact observed on verbal OR = 3.14 (95% CI 1.42, 6.90) P = .005 than performance IQ. Maternal levothyroxine therapy did not reduce the negative impact of perchlorate on offspring IQ., Conclusions: This is the first study using individual-level patient data to study maternal perchlorate exposure and offspring neurodevelopment and suggests that high-end maternal perchlorate levels in hypothyroid/hypothyroxinemic pregnant women have an adverse effect on offspring cognitive development, not affected by maternal levothyroxine therapy. These results require replication in additional studies, including in the euthyroid population.

Background: Although the detrimental effects of severe iodine deficiency are well recognised, the benefits of correcting mild-to-moderate iodine deficiency are uncertain., Objectives: We undertook a systematic review of the impact of iodine supplementation in populations with mild-to-moderate iodine deficiency., Methods: We searched Medline and the Cochrane library for relevant articles published between January 1966 and April 2013, which investigated the effect of iodine supplementation on maternal and newborn thyroid function, infant neurodevelopment and cognitive performance in school-age children. The quality of studies was graded and eligible trials were evaluated in the meta-analysis., Results: Nine randomised controlled trials (RCTs) and eight observational studies met the inclusion criteria. Controlled trials on infant neurodevelopment were lacking; gestational iodine supplementation reduced maternal thyroid volume and serum thyroglobulin and in some studies prevented a rise in serum thyroid-stimulating hormone. None of the intervention trials recorded an excess frequency of thyroid dysfunction in contrast to observational studies. A pooled analysis of two RCTs which measured cognitive function in school-age children showed modest benefits of iodine supplementation on perceptual reasoning (standardised mean difference (SMD) 0.55; 95% CI 0.05, 1.04; P=0.03) and global cognitive index (SMD 0.27; 95% CI 0.10, 0.44; P=0.002) with significant heterogeneity between studies., Conclusion: Iodine supplementation improves some maternal thyroid indices and may benefit aspects of cognitive function in school-age children, even in marginally iodine-deficient areas. Further large prospective controlled studies are urgently required to clarify these findings and quantify the risk/benefits of iodine supplementation in regions previously believed to be iodine sufficient such as the UK.

Context: Overt thyroid disease is associated with profound adverse health outcomes; however, data are conflicting for studies of borderline/subclinical thyroid dysfunction. Many studies of subclinical thyroid disease have had low power and were prone to selection bias. In contrast, large datasets are available from community studies in healthy individuals. Studies of the effects of variation of thyroid function across the reference range on health outcomes in these populations may provide useful information regarding thresholds for treatment of abnormal thyroid function., Evidence Acquisition: MEDLINE and the Cochrane Database of Systematic Reviews and Controlled Trials Register were searched for articles studying the effect of variation in thyroid hormone parameters within the reference range on cardiovascular, bone, metabolic, pregnancy, neurological, and psychological outcomes., Evidence Synthesis: Higher TSH/lower thyroid hormone levels are associated with more cardiovascular risk factors and cardiovascular events and worse metabolic parameters and pregnancy outcomes, whereas lower TSH/higher thyroid hormone levels are associated with reduced bone mineral density and increased fracture risk. The evidence base was good for cardiovascular, metabolic, bone, and pregnancy outcomes; however, high-quality data remained lacking for neurological and psychological outcomes., Conclusions: Common variation in persons with thyroid function in the normal range are associated with adverse health outcomes. These data suggest, by extrapolation, that carefully monitored treatment of even modest elevations of TSH may have substantial health benefits. Appropriately powered large-scale clinical trials analyzing the risks vs benefits of treating subclinical thyroid disease are required to determine whether these benefits can be achieved with levothyroxine therapy.

Objective: There have been conflicting reports on the relationship between thyroid function and mood between studies in subjects on T4 and the general population not on T4. We investigated this relationship in a large catchment area-based study., Design: We analysed data on serum TSH levels and Hospital Anxiety and Depression Scale (HADS) scores from the HUNT 2 study (age > or = 40 years). Following a test for interaction, analyses were performed separately in females on T4 (n = 1265) and in people not on T4 (males n = 9319 and females n = 17 694)., Results: More females on T4 had high depression and anxiety scores than females not on T4 (depression 18.4%vs. 13.0%, P < 0.001, anxiety 23.4%vs. 18.7%, P < 0.001). In those not on T4, there was an inverse association between serum TSH and depression score in males (B coefficient = -0.61, 95% CI -0.91 to -0.24, P = 0.001) though not in females (B coefficient = -0.07, -0.33 to 0.19), and an inverse association between TSH and anxiety score in both genders (B coefficient for males = 0.68, 95% CI -1.04 to -0.32, P < 0.001; females -0.37, 95% CI -0.67 to -0.08, P = 0.01). In contrast, in females on T4, TSH was positively associated with both depression (B coefficient = +0.27, 95% CI 0.02 to 0.51, P < 0.05) and anxiety (B coefficient = +0.29, 95% CI 0.01 to 0.56, P < 0.05)., Conclusions: There is a different relationship between thyroid function and depression and anxiety in females on T4 compared with individuals with no thyroid disease. This group also has a higher prevalence of depression and anxiety.

Graves orbitopathy, also known as thyroid eye disease, affects around 20% of patients with Graves disease. It is disfiguring and has a significant impact on quality of life. In the past, the standard approach was to wait for the disease to "burn-out" and then perform corrective surgeries. However, high-dose steroids have been shown to reduce symptoms and became the standard of care. In 2017, a failed cancer therapeutic called teprotumumab showed remarkable results in reducing proptosis, leading to an explosion of drug repurposing for this condition. One approach involves using monoclonal antibodies to target the neonatal fragment crystallizable receptor (FcRn). A study using batoclimab, an FcRn inhibitor, showed promising results in reducing proptosis, but the trial was stopped due to adverse effects on LDL and serum albumin levels. These findings provide important insights into the disease process and expand therapeutic options. However, the long-term safety and cost-effectiveness of FcRn inhibitors need to be further investigated. Overall, the paradigm for treating Graves orbitopathy is expected to change in the coming years, with surgery and high-dose steroids playing a smaller role. [Extracted from the article]

Background: Thyroid hormones are key determinants of health and well-being. Normal thyroid function is defined according to the standard 95% confidence interval of the disease-free population. Such standard laboratory reference intervals are widely applied in research and clinical practice, irrespective of age. However, thyroid hormones vary with age and current reference intervals may not be appropriate across all age groups. In this review, we summarize the recent literature on age-related variation in thyroid function and discuss important implications of such variation for research and clinical practice. Main text: There is now substantial evidence that normal thyroid status changes with age throughout the course of life. Thyroid stimulating hormone (TSH) concentrations are higher at the extremes of life and show a U-shaped longitudinal trend in iodine sufficient Caucasian populations. Free triiodothyronine (FT3) levels fall with age and appear to play a role in pubertal development, during which it shows a strong relationship with fat mass. Furthermore, the aging process exerts differential effects on the health consequences of thyroid hormone variations. Older individuals with declining thyroid function appear to have survival advantages compared to individuals with normal or high-normal thyroid function. In contrast younger or middle-aged individuals with low-normal thyroid function suffer an increased risk of adverse cardiovascular and metabolic outcomes while those with high-normal function have adverse bone outcomes including osteoporosis and fractures. Conclusion: Thyroid hormone reference intervals have differential effects across age groups. Current reference ranges could potentially lead to inappropriate treatment in older individuals but on the other hand could result in missed opportunities for risk factor modification in the younger and middle-aged groups. Further studies are now needed to determine the validity of age-appropriate reference intervals and to understand the impact of thyroid hormone variations in younger individuals. [ABSTRACT FROM AUTHOR]

Background: Alemtuzumab is an effective therapy for relapsing multiple sclerosis. Autoimmune thyroid events are a common adverse event. Objective: Describe endocrine and multiple sclerosis outcomes over 6 years for alemtuzumab-treated relapsing multiple sclerosis patients in the phase 3 CARE-MS I, II, and extension studies who experienced adverse thyroid events. Methods: Endocrine and multiple sclerosis outcomes were evaluated over 6 years. Thyroid event cases, excluding those pre-existing or occurring after Year 6, were adjudicated retrospectively by expert endocrinologists independently of the sponsor and investigators. Results: Thyroid events were reported for 378/811 (46.6%) alemtuzumab-treated patients. Following adjudication, endocrinologists reached consensus on 286 cases (75.7%). Of these, 39.5% were adjudicated to Graves' disease, 2.5% Hashimoto's disease switching to hyperthyroidism, 15.4% Hashimoto's disease, 4.9% Graves' disease switching to hypothyroidism, 10.1% transient thyroiditis, and 27.6% with uncertain diagnosis; inclusion of anti-thyroid antibody status reduced the number of uncertain diagnoses. Multiple sclerosis outcomes of those with and without thyroid events were similar. Conclusion: Adjudicated thyroid events occurring over 6 years for alemtuzumab-treated relapsing multiple sclerosis patients were primarily autoimmune. Thyroid events were considered manageable and did not affect disease course. Thyroid autoimmunity is a common but manageable adverse event in alemtuzumab-treated relapsing multiple sclerosis patients. ClinicalTrials.gov Registration Numbers: CARE-MS I (NCT00530348); CARE-MS II (NCT00548405); CARE-MS Extension (NCT00930553) [ABSTRACT FROM AUTHOR]

Declarations Competing interests Peter Taylor declares that he is Associate Editor of I Thyroid Research i and that the article was assigned to another Editor to assume responsibility for overseeing peer review. Correction to: Age-related variation in thyroid function - a narrative review highlighting important implications for research and clinical practice Peter Taylor declares that he is Associate Editor of I Thyroid Research i and that the article was assigned to another Editor to assume responsibility for overseeing peer review. [Extracted from the article]