Development of a pediatric differentiated thyroid carcinoma registry within the EuRRECa project: rationale and protocol.

Background: Although differentiated thyroid carcinoma (DTC) is the most frequent endocrine pediatric cancer, it is rare in childhood and adolescence. While tumor persistence and recurrence are not uncommon, mortality remains extremely low. Complications of treatment are however reported in up to 48% of the survivors. Due to the rarity of the disease, current treatment guidelines are predominantly based on the results of small observational retrospective studies and extrapolations from results in adult patients. In order to develop more personalized treatment and follow-up strategies (aiming to reduce complication rates), there is an unmet need for uniform international prospective data collection and clinical trials. Methods and analysis: The European pediatric thyroid carcinoma registry aims to collect clinical data for all patients ≤18 years of age with a confirmed diagnosis of DTC who have been diagnosed, assessed, or treated at a participating site. This registry will be a component of the wider European Registries for Rare Endocrine Conditions project which has close links to Endo-ERN, the European Reference Network for Rare Endocrine Conditions. A multidisciplinary expert working group was formed to develop a minimal dataset comprising information regarding demographic data, diagnosis, treatment, and outcome. We constructed an umbrella-type registry, with a detailed basic dataset. In the future, this may provide the opportunity for research teams to integrate clinical research questions. Ethics and dissemination: Written informed consent will be obtained from all participants and/or their parents/guardians. Summaries and descriptive analyses of the registry will be disseminated via conference presentations and peer-reviewed publications.

Identifying barriers to vaccination intention at walk-in vaccination facilities in deprived neighbourhoods: A cross-sectional survey.

OBJECTIVES: Low COVID-19 vaccination adherence in deprived neighbourhoods is problematic since the prevalence of chronic diseases associated with mortality rates due to COVID-19 is higher in these populations. The aim of this study is to provide an insight about beliefs and considerations relating to vaccination intention among inhabitants of deprived neighbourhoods in the Netherlands. DESIGN: Cross-sectional survey. SETTING: Easily accessible vaccination facilities at markets in deprived neighbourhoods in the Netherlands. PARTICIPANTS: Participants were recruited at three vaccination facilities that were set up at markets in deprived neighbourhoods in Rotterdam. A total of 124 surveys were retained for analysis. MAIN OUTCOME MEASURE: Intention to get vaccinated against COVID-19. RESULTS: The survey was filled out by 124 respondents; 62 % had - prior to visiting the easily accessible locations - intended to get a COVID-19 vaccine and 38 % were hesitant (22.3 % had doubts and 15.7 % did not plan to get vaccinated). Many people mentioned the convenience of an easily accessible location nearby. At the bivariate level, the influence of information from the family was associated with vaccination intention (p < 0.01). In a logistic regression model, both fear of vaccination and fear of side-effects were significantly associated with vaccination intention (ORs 0.56 (CI 0.35-0.89) and 0.47 (CI 0.30-0.73)). CONCLUSION: The accessibility of a vaccination facility, family influence and fear are relevant factors for the intention to get vaccinated against COVID-19 in people living in deprived neighbourhoods. Interventions should address these factors in order to increase vaccination uptake.

Changes in quality of life after thyroidectomy in subjects with thyroid cancer in relation to the dose of levothyroxine.

PURPOSE: Previous studies demonstrated decreased quality of life (QoL) in differentiated thyroid cancer (DTC) survivors and suggested QoL variability related to time from thyroidectomy and levothyroxine dosage. The aims of this study were to evaluate QoL in thyroidectomized subjects in different levothyroxine states and to evaluate the association between TSH and thyroid hormones and QoL. METHODS: Prospective 5-year study enrolling 208 patients thyroidectomized for DTC, studied in one to four times according to levothyroxine dosage: withdrawal (WITHD), complete (C-SUPP) and mild TSH-suppression (M-SUPP), replacement (REPL). Each patient was allowed to participate into the study more than one time. A total of 300 evaluations were collected, consisting of detailed thyroid hormone profile and QoL assessment through the ThyPRO questionnaire. RESULTS: Comparing the four groups, significant differences were found for anxiety, impaired social and daily life and item 12 (overall impact of thyroid disease) domains (p < 0.05). Interestingly, C-SUPP subjects reported the best scores in almost all ThyPRO scales. Significant correlations were found between QoL and pituitary-thyroid axis function, as well as between QoL and gender, being females more affected. At multiple regression analyses fT3 demonstrated to be the best explanatory factor for overall impact of thyroid disease on the patient's life, followed by gender. CONCLUSIONS: TSH-suppressive doses of levothyroxine are more effective in improving QoL in DTC patients after thyroidectomy. These results confirm the urgent need of further studies aimed to define the best treatment of hypothyroidism, effective on well-being and harmless for patients.

New national recommendations for the treatment of pediatric differentiated thyroid carcinoma in the Netherlands.

BACKGROUND: Currently, there are no European recommendations for the management of pediatric thyroid cancer. Other current international guidelines are not completely concordant. In addition, medical regulations differ between, for instance, the US and Europe. We aimed to develop new, easily accessible national recommendations for differentiated thyroid carcinoma (DTC) patients <18 years of age in the Netherlands as a first step toward a harmonized European Recommendation. METHODS: A multidisciplinary working group was formed including pediatric and adult endocrinologists, a pediatric radiologist, a pathologist, endocrine surgeons, pediatric surgeons, pediatric oncologists, nuclear medicine physicians, a clinical geneticist and a patient representative. A systematic literature search was conducted for all existing guidelines and review articles for pediatric DTC from 2000 until February 2019. The Appraisal of Guidelines, Research and Evaluation (AGREE) instrument was used for assessing quality of the articles. All were compared to determine dis- and concordances. The American Thyroid Association (ATA) pediatric guideline 2015 was used as framework to develop specific Dutch recommendations. Discussion points based upon expert opinion and current treatment management of DTC in children in the Netherlands were identified and elaborated. RESULTS: Based on the most recent evidence combined with expert opinion, a 2020 Dutch recommendation for pediatric DTC was written and published as an online interactive decision tree (www.oncoguide.nl). CONCLUSION: Pediatric DTC requires a multidisciplinary approach. The 2020 Dutch Pediatric DTC Recommendation can be used as a starting point for the development of a collaborative European recommendation for treatment of pediatric DTC.

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.

Human chorionic gonadotropin and risk of pre-eclampsia: prospective population-based cohort study.

OBJECTIVES: Abnormal placentation in early pregnancy may play a role in the pathogenesis of pre-eclampsia. Human chorionic gonadotropin (hCG) regulates placental development and angiogenesis and may affect the ratio of soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) in the serum. The aims of this study were to investigate the association of total hCG with the risk of pre-eclampsia and to examine the potential effect of pro- and anti-angiogenic factors on this association. METHODS: This was a population-based prospective cohort study of 7754 women with a singleton pregnancy. Total hCG was measured in the first available sample (median gestational age, 14.4 weeks; 95% range, 10.1-26.1 weeks) and sFlt-1 and PlGF concentrations in early (< 18 weeks; median, 13.2 weeks; 95% range, 9.6-17.6 weeks) and in mid- (18-25 weeks; median, 20.4 weeks; 95% range, 18.5-23.5 weeks) pregnancy. We tested the association of hCG concentration and risk of pre-eclampsia using regression analysis, adjusting for maternal age, ethnicity, body mass index, parity, education level, smoking status and fetal sex. Additionally, we assessed whether this association was affected by the sFlt-1/PlGF ratio. RESULTS: High hCG concentration was associated with a 1.5-2.7-fold increased risk of pre-eclampsia (P = 0.0001), depending on the cut-off used, and with increased sFlt-1/PlGF ratio during early pregnancy (P < 0.0001). The association between high hCG and pre-eclampsia attenuated by roughly 40% after adjustment for early-pregnancy sFlt-1/PlGF ratio (ß-estimate change from 0.19 ± 0.10 (P = 0.052) to 0.12 ± 0.10 (P = 0.22)). CONCLUSIONS: High total hCG concentration in early pregnancy is associated with an increased risk of pre-eclampsia. The effect of high hCG concentration on the balance between pro- and anti-angiogenic factors during pregnancy may have a role in the pathophysiology of pre-eclampsia. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Live birth rate after intrauterine insemination is not different between women with lower quartile versus higher quartile normal range thyroid stimulating hormone levels.

STUDY QUESTION: Does lower quartile normal range thyroid stimulating hormone (TSH) compared to higher quartile normal range in women without thyroid hormone substitution affect live birth rate after a complete IUI treatment series? SUMMARY ANSWER: Lower quartile normal range TSH, in women without thyroid hormone substitution, does not affect live birth rate after a complete intrauterine insemination treatment series compared to higher quartile normal range TSH. WHAT IS KNOWN ALREADY: TSH is historically seen as the most sensitive test for thyroid function. Its distribution is right-skewed. Whether the preconceptional upper reference TSH values in subfertile women should be 2.5 or 4.5 mIU/L is under debate. Studies have shown that IUI patients treated with levothyroxine for TSH levels above 2.5 mIU/L show higher pregnancy rates. However, no adverse outcome is associated with untreated high normal TSH levels studied in first IUI cycles. Thyroid peroxidase antibodies have also impaired outcomes in some studies whereas others have shown an effect only in combination with high normal TSH levels. As a subgroup, patients with unexplained infertility showed increased levels of TSH. This article adds to the value of TSH evaluation and fertility outcome in four quartiles and in the context of a completed IUI treatment modus of a maximum of six inseminations. STUDY DESIGN SIZE DURATION: This is a retrospective cohort study in 909 women undergoing 3588 IUI cycles starting treatment between the first of January 2008 and the first of March 2012. PARTICIPANTS/MATERIALS SETTING METHODS: Women aged 22-45 years with TSH 0.3-4.5 mIU/L without thyroid hormone substitution were included at Amsterdam UMC, Vrije Universiteit, Amsterdam, the Netherlands, an Iodine-sufficient area. The primary endpoint was live birth. Clinical pregnancy, pregnancy loss and ongoing pregnancy were secondary endpoints. Logistic regression was used with the natural logarithm of TSH as a continuous predictor. Chi-square tests and logistic regression were used to compare groups of patients based on TSH values in four quartile TSH groups (0.3-1.21 mIU/L; 1.22-1.75 mIU/L; 1.76-2.34 mIU/L; 2.35-4.5 mIU/L) on basic characteristics and on the endpoints while adjusting for confounders. MAIN RESULTS AND THE ROLE OF CHANCE: Analysis with the natural logarithm of TSH as a continuous variable showed no association with live birth, pregnancy chance or pregnancy loss. There were no differences in any of the outcomes across the quartile TSH level ranges after regression analysis before and after adjusting for age, BMI, use of alcohol, tobacco, use or gonadotrophins, sperm count, diminished ovarian reserve, unexplained infertility and primary or secondary subfertility.The distribution of primary and secondary subfertility and smoking characteristics were remarkably different across the four groups, with proportionally the lowest prevalence of primary subfertility and the highest rate of smoking in the lowest TSH group (0.3-1.20 mIU/L). LIMITATIONS REASONS FOR CAUTION: Unknown values of free thyroxine and thyroid peroxidase antibodies, as well as the retrospective character of the study, limit the clinical interpretability. WIDER IMPLICATIONS OF THE FINDINGS: TSH in the highest quartile range (2.35-4.5 mIU/L) in subfertile women preceding IUI is not associated with a lower live birth rate or rate of clinical and ongoing pregnancy, or with loss of pregnancies, compared to subfertile women with TSH in the lower three quartile groups after complete intrauterine insemination treatment. STUDY FUNDING/COMPETING INTERESTS: The department of Obstetrics and Gynaecology, division of Reproductive Medicine, and of Internal Medicine, division of Endocrinology provided support. There are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Long-term effects of radioiodine treatment on salivary gland function in adult survivors of pediatric differentiated thyroid carcinoma.

Pediatric differentiated thyroid cancer (DTC) is a rare disease. Initial treatment of DTC consists of a (near) total thyroidectomy and radioactive iodine (131I) therapy. Previous studies in adults showed that 131I treatment may result in a reduced salivary gland function. Studies regarding salivary gland function in children treated for DTC are sparse. Our aim was to assess long-term effects of 131I treatment on salivary gland function in survivors of pediatric DTC. Methods: In a nationwide cross-sectional study, salivary gland function of patients treated for pediatric DTC between 1970 and 2013 (>5 years after diagnosis, ≥18 years old at time of evaluation) was studied. Salivary gland function was assessed by sialometry, sialochemistry and a xerostomia inventory. Salivary gland dysfunction was defined as unstimulated whole saliva flow ≤0.2mL/min and/or a stimulated whole saliva flow ≤0.7 mL/min. Results: Sixty-five patients (median age at evaluation 33 [IQR, 25-40] years, 86.2% female, median follow-up period 11 [IQR, 6-22] years) underwent 131I treatment. Median cumulative 131I activity was 5.88 [IQR, 2.92-12.95] GBq, 47.7% underwent multiple 131I administrations. Salivary gland dysfunction was present in 30 (47.6%) patients. Levels of amylase and total protein in saliva were reduced. Moderate to severe xerostomia was present in 22 (35.5%) patients. Stimulated salivary secretion was lower and severity of xerostomia complaints higher in patients treated with higher cumulative 131I activity. Conclusion: In survivors of pediatric DTC, clinically significant salivary gland dysfunction was found in 35.5% and was related to the cumulative 131I activity of the treatment.

Study protocol: a randomised controlled trial on the clinical effects of levothyroxine treatment for subclinical hypothyroidism in people aged 80 years and over.

BACKGROUND: Subclinical hypothyroidism is common in older people and its contribution to health and disease needs to be elucidated further. Observational and clinical trial data on the clinical effects of subclinical hypothyroidism in persons aged 80 years and over is inconclusive, with some studies suggesting harm and some suggesting benefits, translating into equipoise whether levothyroxine therapy provides clinical benefits. This manuscript describes the study protocol for the Institute for Evidence-Based Medicine in Old Age (IEMO) 80-plus thyroid trial to generate the necessary evidence base. METHODS: The IEMO 80-plus thyroid trial was explicitly designed as an ancillary experiment to the Thyroid hormone Replacement for Untreated older adults with Subclinical hypothyroidism randomised placebo controlled Trial (TRUST) with a near identical protocol and shared research infrastructure. Outcomes will be presented separately for the IEMO and TRUST 80-plus groups, as well as a pre-planned combined analysis of the 145 participants included in the IEMO trial and the 146 participants from the TRUST thyroid trial aged 80 years and over. The IEMO 80-plus thyroid trial is a multi-centre randomised double-blind placebo-controlled parallel group trial of levothyroxine treatment in community-dwelling participants aged 80 years and over with persistent subclinical hypothyroidism (TSH ≥4.6 and ≤ 19.9 mU/L and fT4 within laboratory reference ranges). Participants are randomised to levothyroxine 25 or 50 micrograms daily or matching placebo with dose titrations according to TSH levels, for a minimum follow-up of one and a maximum of three years. Primary study endpoints: hypothyroid physical symptoms and tiredness on the thyroid-related quality of life patient-reported outcome (ThyPRO) at one year. Secondary endpoints: generic quality of life, executive cognitive function, handgrip strength, functional ability, blood pressure, weight, body mass index, and mortality. Adverse events will be recorded with specific interest on cardiovascular endpoints such as atrial fibrillation and heart failure. DISCUSSION: The combined analysis of participants in the IEMO 80-plus thyroid trial with the participants aged over 80 in the TRUST trial will provide the largest experimental evidence base on multimodal effects of levothyroxine treatment in 80-plus persons to date. TRIAL REGISTRATION: Nederlands (Dutch) Trial Register: NTR3851 (12-02-2013), EudraCT: 2012-004160-22 (17-02-2013), ABR-41259.058.13 (12-02-2013).

Balancing the benefits and harms of thyroid cancer surveillance in survivors of Childhood, adolescent and young adult cancer: Recommendations from the international Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium.

Radiation exposure to the thyroid gland during treatment of childhood, adolescent and young adult cancer (CAYAC) may cause differentiated thyroid cancer (DTC). Surveillance recommendations for DTC vary considerably, causing uncertainty about optimum screening practices. The International Late Effects of Childhood Cancer Guideline Harmonization Group, in collaboration with the PanCareSurFup Consortium, developed consensus recommendations for thyroid cancer surveillance in CAYAC survivors. These recommendations were developed by an international multidisciplinary panel that included 33 experts in relevant medical specialties who used a consistent and transparent process. Recommendations were graded according to the strength of underlying evidence and potential benefit gained by early detection and appropriate management. Of the two available surveillance strategies, thyroid ultrasound and neck palpation, neither was shown to be superior. Consequently, a decision aid was formulated to guide the health care provider in counseling the survivor. The recommendations highlight the need for shared decision making regarding whether to undergo surveillance for DTC and in the choice of surveillance modality.

Association between subclinical thyroid dysfunction and change in bone mineral density in prospective cohorts.

BACKGROUND: Subclinical hyperthyroidism (SHyper) has been associated with increased risk of hip and other fractures, but the linking mechanisms remain unclear. OBJECTIVE: To investigate the association between subclinical thyroid dysfunction and bone loss. METHODS: Individual participant data analysis was performed after a systematic literature search in MEDLINE/EMBASE (1946-2016). Two reviewers independently screened and selected prospective cohorts providing baseline thyroid status and serial bone mineral density (BMD) measurements. We classified thyroid status as euthyroidism (thyroid-stimulating hormone [TSH] 0.45-4.49 mIU/L), SHyper (TSH < 0.45 mIU/L) and subclinical hypothyroidism (SHypo, TSH ≥ 4.50-19.99 mIU/L) both with normal free thyroxine levels. Our primary outcome was annualized percentage BMD change (%ΔBMD) from serial dual X-ray absorptiometry scans of the femoral neck, total hip and lumbar spine, obtained from multivariable regression in a random-effects two-step approach. RESULTS: Amongst 5458 individuals (median age 72 years, 49.1% women) from six prospective cohorts, 451 (8.3%) had SHypo and 284 (5.2%) had SHyper. During 36 569 person-years of follow-up, those with SHyper had a greater annual bone loss at the femoral neck versus euthyroidism: %ΔBMD = -0.18 (95% CI: -0.34, -0.02; I2 = 0%), with a nonstatistically significant pattern at the total hip: %ΔBMD = -0.14 (95% CI: -0.38, 0.10; I2 = 53%), but not at the lumbar spine: %ΔBMD = 0.03 (95% CI: -0.30, 0.36; I2 = 25%); especially participants with TSH < 0.10 mIU/L showed an increased bone loss in the femoral neck (%Δ BMD = -0.59; [95% CI: -0.99, -0.19]) and total hip region (%ΔBMD = -0.46 [95% CI: -1.05, -0.13]). In contrast, SHypo was not associated with bone loss at any site. CONCLUSION: Amongst adults, SHyper was associated with increased femoral neck bone loss, potentially contributing to the increased fracture risk.

Thyrotoxic periodic paralysis: an unusual presentation of hyperthyroidism.

Thyrotoxic periodic paralysis (TPP) is a complication of hyperthyroidism among Asians, characterised by sudden onset of hypokalaemia and muscle paralysis. Several factors may contribute to a delay in diagnosis, including the subtlety of hyperthyroidism, the transient nature of the events and the rarity of this disease in the West. As life-threatening arrhythmias may occur during an attack, awareness among physicians is necessary for early recognition and treatment. Advances have been made in understanding the pathophysiological mechanism leading to hypokalaemia, which include recently identified mutations of the inwardly rectifying potassium channel Kir2.6. Treatment includes the supplementation of potassium, a nonselective beta-blocker, and ultimately treatment of the underlying hyperthyroidism. Here we report three cases of TPP in the Netherlands, and review the literature on clinical features, pathophysiological hypothesis and treatment.

Thyroid Function during Early Life and Dental Development.

Children with low levels of thyroid hormones (hypothyroidism) have delayed tooth eruption, enamel hypoplasia, micrognathia, and anterior open bite, whereas children with hyperthyroidism may suffer from accelerated tooth eruption, maxillary, and mandibular osteoporosis. However, it is still unknown whether thyroid function variations within the normal or subclinical range also have an impact on hard dental tissues in healthy children. The objective of this study was, therefore, to investigate the association between thyroid function from the fetal period until early childhood and dental development at school age. This study is embedded in the Generation R Study, a population-based cohort study established in Rotterdam, the Netherlands. Maternal thyroid function (thyroid-stimulating hormone [TSH], free thyroxine [FT4], and thyroid peroxidase antibody [TPOAb] concentrations) was measured during early pregnancy, and thyroid function of the offspring (TSH and FT4) was measured in cord blood at birth and in early childhood (6 y). Dental development was assessed from panoramic radiographs of children of school-going age (9 y). In total, 2,387 to 2,706 subjects were available for the multivariable linear regression analysis, depending on the point in time of thyroid function measurement. There was an inverse association between cord blood and early childhood TSH concentrations with dental development, with a -0.06 lower standard deviation (SD) per 1 mU/L of TSH (95% confidence interval [CI], -0.11 to -0.01) and a -0.06 lower SD per 1 mU/L of TSH (95% CI, -0.11 to 0.00), respectively. There was no association between the maternal thyroid function during pregnancy and the dental development score of the child. However, TPOAb-positive mothers had children with a -0.20 SD (adjusted 95% CI, -0.35 to -0.04) lower dental development score compared with TPOAb-negative mothers. The findings of this study suggest that the thyroid hormone is involved in the maturation of teeth from the early stages of life onward.

[What is a normal thyroid function?] / Wat is een 'normale' schildklierfunctie?

Thyroid dysfunction is currently defined by a TSH value outside of its statistically established normal range. This definition does not take patients' individual symptoms or long-term risk of disease into account. However, increasing evidence shows that certain variations in thyroid function, even within the normal range, are associated with several adverse clinical outcomes. Also, subclinical thyroid dysfunction in patients, defined by a TSH outside of the normal range and free thyroxine within the normal range, has been shown to be accompanied by more thyroid-related symptoms when compared to the general population. This raises the question whether normal ranges are truly normal, and whether a new definition of thyroid function and thyroid dysfunction should be developed.

The association of maternal thyroid function with placental hemodynamics.

STUDY QUESTION: What is the clinical association of maternal thyroid function with placental hemodynamic function? SUMMARY ANSWER: A higher free thyroxine (FT4) concentration in early pregnancy is associated with higher placental vascular resistance. WHAT IS KNOWN ALREADY: Suboptimal placental function is associated with preeclampsia (which, in turn, further deteriorates placental hemodynamics and impairs the fetal blood supply), fetal growth restriction and premature delivery. Studies have suggested that thyroid hormone (TH) has a role in placental development through effects on trophoblast proliferation and invasion. STUDY DESIGN, SIZE, DURATION: This study was embedded in The Generation R cohort, a population-based prospective study from early fetal life onwards in Rotterdam, the Netherlands. In total, 7069 mothers with expected delivery date between April 2002 and January 2006 were enrolled during early pregnancy. PARTICIPANTS/MATERIALS, SETTING, METHOD: Thyroid-stimulating hormone (TSH) and free thyroxine (FT4) concentrations were measured during early pregnancy (median 13.4 weeks, 95% range 9.7-17.6 weeks). Placental function was assessed by Doppler ultrasound via measurement of arterial vascular resistance, i.e. umbilical artery pulsatility index (PI) and uterine artery resistance index (RI) (both measured twice, between 18-25th and after 25th gestational weeks) and the presence of uterine artery notching (once after the 25th gestational week) in 5184 pregnant women. MAIN RESULTS AND THE ROLE OF CHANCE: FT4 was positively linearly associated with umbilical artery PI in the second and third trimesters as well as with uterine artery RI in the second trimester and the risk of uterine artery notching in the third trimester (P < 0.05 for all). The association of thyroid function with preeclampsia and birth weight was partially mediated through changes in placental function, with the percentages of mediated effects being 10.4% and 12.5%, respectively. LIMITATIONS, REASONS FOR CAUTION: A potential limitation is the availability of only a single time point for TH measurements and different numbers of missing placental ultrasound measurements for the adverse outcomes. WIDER IMPLICATIONS OF THE FINDINGS: A higher FT4 concentration in early pregnancy is associated with higher vascular resistance in the second and third trimesters in both the maternal and fetal placental compartment. These effects on placental function might explain the association of FT4 with adverse pregnancy outcomes, including preeclampsia and fetal growth restriction. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by a fellowship from ERAWEB, a project funded by the European Commission (to M.B.) and by clinical fellowship from The Netherlands Organization for Health Research and Development (ZonMw), Project 90700412 (to R.P.P.). The authors have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Exome-sequencing in a large population-based study reveals a rare Asn396Ser variant in the LIPG gene associated with depressive symptoms.

Despite a substantial genetic component, efforts to identify common genetic variation underlying depression have largely been unsuccessful. In the current study we aimed to identify rare genetic variants that might have large effects on depression in the general population. Using high-coverage exome-sequencing, we studied the exonic variants in 1265 individuals from the Rotterdam study (RS), who were assessed for depressive symptoms. We identified a missense Asn396Ser mutation (rs77960347) in the endothelial lipase (LIPG) gene, occurring with an allele frequency of 1% in the general population, which was significantly associated with depressive symptoms (P-value=5.2 × 10-08, ß=7.2). Replication in three independent data sets (N=3612) confirmed the association of Asn396Ser (P-value=7.1 × 10-03, ß=2.55) with depressive symptoms. LIPG is predicted to have enzymatic function in steroid biosynthesis, cholesterol biosynthesis and thyroid hormone metabolic processes. The Asn396Ser variant is predicted to have a damaging effect on the function of LIPG. Within the discovery population, carriers also showed an increased burden of white matter lesions (P-value=3.3 × 10-02) and a higher risk of Alzheimer's disease (odds ratio=2.01; P-value=2.8 × 10-02) compared with the non-carriers. Together, these findings implicate the Asn396Ser variant of LIPG in the pathogenesis of depressive symptoms in the general population.

[Radiofrequency ablation of a symptomatic benign thyroid nodule]. / Radiofrequente ablatie van symptomatische benigne schildkliernodus.

Radiofrequency ablation (RFA) enables the ablation of selected tissue by means of heat. For the first time in the Netherlands, RFA is being used to treat patients with benign thyroid nodules. RFA is able to reduce the volume of a nodule that may be causing cosmetic complaints or problems due to mass effect. This avoids the need for surgery or treatment with radioactive iodine in this benign condition. The average reduction in size is 80% in the first year, leading to a considerable decrease in both symptomatic and cosmetic complaints. At Erasmus Medical Centre, Rotterdam, the Netherlands, this technique has been introduced in accordance with current guidelines, and it is expected that other centres of excellence will follow in implementing it. It is important that the initial experiences with this technique in the Netherlands in terms of effectiveness, risks and patient satisfaction should be monitored before RFA becomes routine treatment.

Risk factors for subsequent endocrine-related cancer in childhood cancer survivors.

Long-term adverse health conditions, including secondary malignant neoplasms, are common in childhood cancer survivors. Although mortality attributable to secondary malignancies declined over the past decades, the risk for developing a solid secondary malignant neoplasm did not. Endocrine-related malignancies are among the most common secondary malignant neoplasms observed in childhood cancer survivors. In this systematic review, we describe risk factors for secondary malignant neoplasms of the breast and thyroid, since these are the most common secondary endocrine-related malignancies in childhood cancer survivors. Radiotherapy is the most important risk factor for secondary breast and thyroid cancer in childhood cancer survivors. Breast cancer risk is especially increased in survivors of Hodgkin lymphoma who received moderate- to high-dosed mantle field irradiation. Recent studies also demonstrated an increased risk after lower-dose irradiation in other radiation fields for other childhood cancer subtypes. Premature ovarian insufficiency may protect against radiation-induced breast cancer. Although evidence is weak, estrogen-progestin replacement therapy does not seem to be associated with an increased breast cancer risk in premature ovarian-insufficient childhood cancer survivors. Radiotherapy involving the thyroid gland increases the risk for secondary differentiated thyroid carcinoma, as well as benign thyroid nodules. Currently available studies on secondary malignant neoplasms in childhood cancer survivors are limited by short follow-up durations and assessed before treatment regimens. In addition, studies on risk-modifying effects of environmental and lifestyle factors are lacking. Risk-modifying effects of premature ovarian insufficiency and estrogen-progestin replacement therapy on radiation-induced breast cancer require further study.

Thyroid hormone and its metabolites in relation to quality of life in patients treated for differentiated thyroid cancer.

BACKGROUND: Levothyroxine (LT4) is the standard of care in patients with hypothyroidism. Despite this replacement therapy, quality of life (QoL) remains impaired in a substantial amount of patients. The reasons for this are still a matter of debate. Suggested causes include lack of endogenous T3 secretion by the thyroid, changes in other thyroid hormone metabolites and interference by autoimmune processes. OBJECTIVE: To investigate the association between thyroid function tests (TFTs) and QoL in patients with a history of differentiated thyroid cancer on LT4 monotherapy. These patients lack endogenous thyroidal T3 secretion in the absence of autoimmune disease. MATERIALS AND METHODS: This is a cross-sectional study in 143 patients (69·2% female). Initial therapy consisted of total thyroidectomy followed by radioiodine ablation minimally one year before inclusion. We assessed health-related QoL (RAND-36), thyroid-specific QoL (ThyPRO) and fatigue with the Multidimensional Fatigue Inventory. Extensive TFTs were assessed, including 3,5-diiodo-L-thyronine (3,5-T2). RESULTS: Mean age was 50·2 years and mean time since diagnosis was 8·4 years. Median TSH was 0·042 mU/l, total T4 145·0 nmol/l, free T4 25·6 pmol/l, total T3 1·93 nmol/l, reverse T3 0·53 nmol/l and 3,5-T2 0·86 nmol/l. Multiple linear regression analyses did not show any association between QoL and the different TFTs, including T4/T3 and 3,5-T2/T3 ratios reflecting peripheral metabolism. CONCLUSION: We did not find any association between TFTs and QoL in athyreotic patients on LT4 monotherapy. Our data do not provide evidence that a slight increase in dose improves fatigue or well-being in hypothyroid patients on LT4 therapy.