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Background The association of thyroid function with risk of type 2 diabetes remains elusive. We aimed to investigate the association of thyroid function with incident diabetes and progression from prediabetes to diabetes in a population-based prospective cohort study. Methods We included 8452 participants (mean age 65 years) with thyroid function measurement, defined by thyroid-stimulating hormone (TSH) and free thyroxine (FT4), and longitudinal assessment of diabetes incidence. Cox-models were used to investigate the association of TSH and FT4 with diabetes and progression from prediabetes to diabetes. Multivariable models were adjusted for age, sex, high-density lipoprotein cholesterol, and glucose at baseline, amongst others. Results During a mean follow-up of 7.9 years, 798 diabetes cases occurred. Higher TSH levels were associated with a higher diabetes risk (hazard ratio [HR] 1.13; 95 % confidence interval [CI], 1.08–1.18, per logTSH), even within the reference range of thyroid function (HR 1.24; 95 % CI, 1.06–1.45). Higher FT4 levels were associated with a lower diabetes risk amongst all participants (HR 0.96; 95 % CI, 0.93–0.99, per 1 pmol/L) and in participants within the reference range of thyroid function (HR 0.96; 95 % CI, 0.92–0.99). The risk of progression from prediabetes to diabetes was higher with low-normal thyroid function (HR 1.32; 95 % CI, 1.06–1.64 for TSH and HR 0.91; 95 % CI, 0.86–0.97 for FT4). Absolute risk of developing diabetes type 2 in participants with prediabetes decreased from 35 % to almost 15 % with higher FT4 levels within the normal range. Conclusions Low and low-normal thyroid function are risk factors for incident diabetes, especially in individuals with prediabetes. Future studies should investigate whether screening for and treatment of (subclinical) hypothyroidism is beneficial in subjects at risk of developing diabetes.

Human chorionic gonadotropin (hCG) is a pregnancy hormone secreted by the placental synctiotrophoblast cell layer that has been linked to fetal growth and various placental, uterine and fetal functions. In order to investigate the effects of hCG on clinical endpoints, knowledge on reference range (RR) methodology and determinants of gestational hCG levels is crucial. Moreover, a better understanding of gestational hCG physiology can improve current screening programs and future clinical management. Serum total hCG levels were determined in 8195 women participating in the Generation R Study. Gestational age specific RRs using ' ultrasound derived gestational age' (US RRs) were calculated and compared with 'last menstrual period derived gestational age' (LMP RRs) and a model-based RR. We also investigated which pregnancy characteristics were associated with hCG levels. Compared to the US RRs, the LMP RRs were lower, most notably for the median and lower limit levels. No considerable differences were found between RRs calculated in the general population or in uncomplicated pregnancies only. Maternal smoking, BMI, parity, ethnicity, fetal gender, placental weight and hyperemesis gravidarum symptoms were associated with total hCG. We provide gestational RRs for total hCG and show that total hCG values and RR cut-offs during pregnancy vary depending on pregnancy dating methodology. This is likely due to the influence of hCG on embryonic growth, suggesting that ultrasound based pregnancy dating might be less reliable in women with high/low hCG levels. Furthermore, we identify different pregnancy characteristics that influence total hCG levels considerably and should therefore be accounted for in clinical studies.

Key Points Studies published during the past decade have enabled researchers to gain new insights into the diagnosis, physiology and treatment of thyroid disease during pregnancy. The previously recommended TSH cut-offs of 2.5 mU/l or 3.0 mU/l are too low and are likely to lead to overdiagnosis and overtreatment of thyroid disease during pregnancy. The combination of thyroid peroxidase-antibody positivity and a high concentration of TSH seems to synergistically increase the risk of adverse pregnancy outcomes. Substantial new evidence supports the important role of thyroid hormone for fetal neurodevelopment. New studies indicate that in patients treated with levothyroxine, titration to thyroid hormone concentrations in the higher end of the normal range might carry a risk of overtreatment. Particularly during early pregnancy, treatment with methimazole (thiamazole) or propylthiouracil might increase the risk of fetal anomalies, and clinicians should consider the cessation of low-dose regimens. Thyroid dysfunction is associated with adverse obstetric and child development outcomes. Here, Tim Korevaar and colleagues put studies from the past decade on reference ranges, thyroid dysfunction determinants, adverse outcome risks and treatment options into perspective. Adequate thyroid hormone availability is important for an uncomplicated pregnancy and optimal fetal growth and development. Overt thyroid disease is associated with a wide range of adverse obstetric and child development outcomes. An increasing number of studies now indicate that milder forms of thyroid dysfunction are also associated with these adverse pregnancy outcomes. The definitions of both overt and subclinical thyroid dysfunction have changed considerably over the past few years, as new data indicate that the commonly used fixed upper limits of 2.5 mU/l or 3.0 mU/l for thyroid-stimulating hormone (TSH) are too low to define an abnormal thyroid function. Furthermore, some studies now show that the reference ranges are not necessarily the best cut-off for identifying pregnancies at high risk of adverse outcomes. In addition, data suggest that thyroid peroxidase autoantibody positivity and high or low concentrations of human chorionic gonadotropin seem to have a more prominent role in the interpretation of thyroid dysfunction than previously thought. Data on the effects of thyroid disease treatment are lacking, but some studies indicate that clinicians should be aware of the potential for overtreatment with levothyroxine. Here, we put studies from the past decade on reference ranges for TSH, determinants of thyroid dysfunction, risks of adverse outcomes and options for treatment into perspective. In addition, we provide an overview of the current views on thyroid physiology during pregnancy and discuss strategies to identify high-risk individuals who might benefit from levothyroxine treatment.

This is an invitation letter for the principal investigators and cohort studies to join the Consortium on Thyroid and Pregnancy. The inclusion criteria are population-based cohorts with data on maternal thyroid function during pregnancy and any measurement of known groups of endocrine disrupting chemicals.

Background The SARS-CoV-2 outbreak has resulted in a tremendous increase in hospital and intensive care unit (ICU) admissions all over the world. Patients with severe coronavirus disease 2019 (COVID-19) warranting ICU treatment usually have prolonged mechanical ventilation and are expected to be prone to develop psychological impairments, such as post-traumatic stress disorder (PTSD), anxiety and depression, which negatively impact quality of life. To date, no effective treatment strategy is available. In the current trial, we aim to assess the effect of an ICU-specific virtual reality (ICU-VR) intervention on psychological well-being and quality of life after COVID-19 ICU treatment. Methods In this multicentre, randomized controlled trial, we aim to examine whether COVID-19-specific ICU-VR, offered 3 months after hospital discharge, improves psychological well-being and quality of life. Secondary objectives are, firstly, to examine the intra-group changes in psychological well-being and quality of life and the inter-group differences in psychological well-being and quality of life during follow-up, up to 12 months after hospital discharge, and secondly, to examine patients’ satisfaction with and rating of ICU care and aftercare and patients’ perspectives on ICU-VR. Eighty adult patients treated for COVID-19 in the mixed-surgical ICUs of four hospitals in Rotterdam, the Netherlands, will be included and randomized (1:1) to either early or late ICU-VR between June 29 and December 31, 2020. Patients randomized to early ICU-VR will receive the ICU-VR intervention during an outpatient clinic visit 3 months after hospital discharge, whereas patients randomized to late ICU-VR will receive ICU-VR 6 months after hospital discharge. Primary outcomes of this study are psychological well-being, assessed using the Impact of Event Scale–Revised (IES-R) and the Hospital Anxiety and Depression Scale (HADS), and quality of life, assessed using the European Quality of Life 5 Dimensions (EQ-5D) and RAND-36 questionnaires, up to 6 months after hospital discharge. Discussion Currently, an effective treatment for psychological sequelae after ICU treatment for specific illnesses is unavailable. Results from this study will provide insight whether virtual reality is a modality that can be used in ICU aftercare to improve psychological well-being and quality of life, or satisfaction, after ICU treatment for specific illnesses such as COVID-19. Trial registration This trial has been retrospectively registered on the Netherlands Trial Register on August 14, 2020 ( NL8835 ).

Although the consequences of severe iodine deficiency are beyond doubt, the effects of mild to moderate iodine deficiency in pregnancy on child neurodevelopment are less well established. To study the association between maternal iodine status during pregnancy and child IQ and identify vulnerable time windows of exposure to suboptimal iodine availability. Meta-analysis of individual participant data from three prospective population-based birth cohorts: Generation R (Netherlands), INMA (Spain), and ALSPAC (United Kingdom); pregnant women were enrolled between 2002 and 2006, 2003 and 2008, and 1990 and 1992, respectively. General community. 6180 mother-child pairs with measures of urinary iodine and creatinine concentrations in pregnancy and child IQ. Exclusion criteria were multiple pregnancies, fertility treatment, medication affecting the thyroid, and preexisting thyroid disease. Child nonverbal and verbal IQ assessed at 1.5 to 8 years of age. There was a positive curvilinear association of urinary iodine/creatinine ratio (UI/Creat) with mean verbal IQ only. UI/Creat <150 µg/g was not associated with lower nonverbal IQ (-0.6 point; 95% CI: -1.7 to 0.4 points; P = 0.246) or lower verbal IQ (-0.6 point; 95% CI: -1.3 to 0.1 points; P = 0.082). Stratified analyses showed that the association of UI/Creat with verbal IQ was only present up to 14 weeks of gestation. Fetal brain development is vulnerable to mild to moderate iodine deficiency, particularly in the first trimester. Our results show that potential randomized controlled trials investigating the effect of iodine supplementation in women with mild to moderate iodine deficiency on child neurodevelopment should begin supplementation not later than the first trimester.

Previous studies suggest that maternal thyroid function affects fetal growth, but the association between combined thyroid hormones from early to late pregnancy and newborn birth weight remains unknown. To explore the association of maternal thyroid function during early and late pregnancy with birth weight. A large prospective cohort study of a Chinese population. This study recruited pregnant women who underwent first-trimester prenatal screenings at the International Peace Maternity and Child Health Hospital between January 2013 and December 2016. This study enrolled 46,186 mothers in whom TSH, free thyroxine (FT4), T3, and thyroid peroxidase antibody concentrations were measured in the first and third trimesters and in whom data on birth weight were available. Birth weight, small for gestational age, large for gestational age (LGA). A higher TSH or FT4 concentration, or a lower T3 concentration, during the first or third trimester was associated with a lower birth weight. The lowest percentiles of maternal FT4 (FT4 < 2.5th percentile) in both trimesters were associated with a 0.34-SD higher birth weight. The effect estimates were greater in those in the first trimester (0.23 SD) or in the third trimester (0.17 SD). The association of maternal TSH and FT4 with birth weight differed according to fetal sex. Persistently low FT4 concentrations throughout pregnancy were associated with higher birth weight and an increased risk of LGA. Based on these findings, we recommend monitoring mildly altered concentrations of thyroid hormone throughout pregnancy.

Abstract Context Low maternal free T4 (FT4) has been associated with poor child neurodevelopment in some single-center studies. Evidence remains scarce for the potential adverse effects of high FT4 and whether associations differ in countries with different iodine status. Objective To assess the association of maternal thyroid function in early pregnancy with child neurodevelopment in countries with a different iodine status. Design, Setting, and Participants Meta-analysis of individual participant data from 9036 mother–child pairs from three prospective population-based birth cohorts: INMA [Infancia y Medio Ambiente (Environment and Childhood project) (Spain)], Generation R (Netherlands), and ALSPAC (Avon Longitudinal Study of Parents and Children, United Kingdom). The exclusion criteria were multiple pregnancies, fertility treatments, thyroid-interfering medication usage, and known thyroid disease. Main Outcomes Child nonverbal IQ at 5 to 8 years of age, verbal IQ at 1.5 to 8 years of age, and autistic traits within the clinical range at 5 to 8 years of age. Results FT4 <2.5th percentile was associated with a 3.9-point (95% CI, −5.7 to −2.2) lower nonverbal IQ and a 2.1-point (95% CI, −4.0 to −0.1) lower verbal IQ. A suggestive association of hypothyroxinemia with a greater risk of autistic traits was observed. FT4 >97.5th percentile was associated with a 1.9-fold (95% CI, 1.0 to 3.4) greater risk of autistic traits. No independent associations were found with TSH. Conclusions Low maternal FT4 was consistently associated with a lower IQ across the cohorts. Further studies are needed to replicate the findings of autistic traits and investigate the potential modifying role of maternal iodine status. FT4 seems a reliable marker of fetal thyroid state in early pregnancy, regardless of the type of immunoassay. This study confirms that low FT4, but not TSH, during early pregnancy is associated with a lower IQ. We report a suggestive association of hypothyroxinemia and high maternal FT4 with autistic traits.

Objectives: We aimed to develop and validate a simple, easy-to-use risk stratification tool to use in the diagnosis of gestational diabetes mellitus (GDM) to triage those more likely to require insulin treatment. Methods: Using an audit of patients with GDM in 2019, multivariable logistic regression was used to select variables and develop a prediction model for insulin requirement. A stratification tool was developed by dichotomising these selected variables; its performance was assessed with an internal cohort from 2021 and externally from patients managed at a separate hospital. Results: Patients with a higher fasting blood glucose concentration (OR 2.41, 95% CI 1.84–3.15) and higher booking body mass index (OR 1.48, 95% CI 1.07–2.03) were more likely to require insulin therapy whilst a later gestational-weeks-at-diagnosis value gave a lower risk of insulin therapy (OR 0.71, 95% CI 0.62–0.81 per week). The low-risk group for insulin requirement was defined thus: fasting blood glucose < 5.6 mmol/L, booking BMI < 30 kg/m2, and gestational weeks at diagnosis ≥ 24 weeks. This classification had a negative predictive value (NPV) of 94% for insulin requirement, with a sensitivity of 84% and specificity of 56% in the development cohort. Similarly, in the internal and external validation cohorts, the NPVs were 93 and 90%, with sensitivity values of 77 and 78%, respectively. Conclusions: This study developed a pragmatic tool with three criteria for stratifying the GDM group not requiring insulin treatment, with successful validation for clinical use.

Context Thyroid hormones play an essential role in lipid metabolism. The association of thyroid function and dyslipidemia in women has been mostly studied in the general population, and epidemiological evidence during pregnancy is scarce. Objective We investigated the association of preconception thyroid function and autoimmunity with serum lipid biomarkers during pregnancy among 142 pregnant women enrolled in the Environment and Reproductive Health (EARTH) Study (2005 – 2017) who were seeking treatment at a fertility center. Methods Before conception, we measured biomarkers of thyroid function and autoimmunity including thyroid stimulating hormone (TSH), free thyroxine (fT 4 ), total thyroxine (TT 4 ), free triiodothyronine (fT 3 ), total triiodothyronine (TT 3 ), thyroid peroxidase antibodies (TPOAb), and thyroglobulin antibodies (TgAb). During pregnancy, we assessed lipid biomarkers including serum levels of total triglycerides (TG), total cholesterol (TC), high-density lipoprotein (HDL), non-HDL, and low-density lipoprotein (LDL) cholesterol. Linear regression models were used to study these associations while adjusting for age, body mass index, physical activity, multifetal gestation, infertility diagnosis and trimester of lipid measurement. Results We observed a negative association between preconception serum TT 3 and HDL cholesterol levels during pregnancy (β estimate = -8.6, 95% CI = -16.2, -1.1), and a smaller negative association for TT 4 with HDL (β estimate = -0.2, 95% CI = -4.0, 0.0). When stratified by trimester, these associations were stronger for those with lipids measured in the 3 rd trimesters but were not observed for lipids measured in the 1 st and 2 nd trimesters. We also found that each 0.1 unit increase in the preconception fT 3 : fT 4 ratio was associated with higher total cholesterol (β estimate = 32.4, 95% CI = 1.93, 62.6), non-HDL (β estimate = 35.8, 95% CI = 5.63, 65.9) and LDL (β estimate = 32.1, 95% CI = 4.48, 59.7) cholesterol in 3 rd trimester, but no association for those with lipids measured in earlier trimesters. No other associations were found for the other examined exposures and outcomes. Conclusions This study showed that some preconception biomarkers of thyroid function were associated with serum lipid levels during pregnancy. These results highlight the importance of thyroid function during the preconception window, and its potential impact on cholesterol levels at different time periods in the pregnancy.