Adequate thyroid hormone availability during pregnancy is necessary for optimal fetal brain development. During the first 18-20 weeks of gestation, fetal thyroid hormone availability largely depends ...on the placental transfer of maternal thyroxine. Although various studies have shown that maternal thyroid dysfunction is associated with suboptimal child neurodevelopmental outcomes, the most vulnerable time window remains to be identified. The aim of this study is to examine the association of maternal thyroid function with child brain morphology and to study whether any association depends on the timing of thyroid assessment.
This prospective cohort study was part of the Generation R Study in Rotterdam, Netherlands, with a prospective population-based birth cohort. Pregnant women living in Rotterdam with an expected delivery date between April 1, 2002, and Jan 1, 2006, were eligible. Other inclusion criteria were maternal serum thyroid-stimulating hormone (TSH) and free thyroxine (FT
) measurement in early or mid-pregnancy (≤18 weeks) and available brain MRI data for child at age 10 years. Exclusion criteria were pre-existing thyroid disorder, thyroid disorder treatment, twin pregnancy, in-vitro fertilisation-induced pregnancy, and suboptimal-quality MRI data or major incidental finding on MRI. The main outcome was the association between maternal TSH and FT
concentrations with brain MRI outcomes of children. Regression analyses accounted for gestational age at blood sampling, maternal age, ethnicity, education level, smoking, thyroid peroxidase antibody positivity, child sex, age at MRI, and total intracranial volume. Effect modification by gestational age at blood sampling was also investigated.
Between Dec 1, 2001, and June 30, 2005, 7069 women were enrolled during early or mid-pregnancy (≤18 weeks of gestation), of whom 5088 were not included because they did not have available data on maternal serum TSH or FT
concentrations (n=1175), their child did not have brain MRI done (n=3377), or they met exclusion criteria (n=536). Thus, 1981 mother-child pairs were included in the study, with TSH and FT
concentrations measured during pregnancy at a median of 13·1 weeks of gestation (IQR 12·1-14·5) and offspring brain morphology assessed by MRI at a median age of 9·9 years (9·7-10·2). Maternal TSH had an inverted U-shaped association with offspring total grey matter volume (p=0·007) and with cortical grey matter volume (p=0·022). The association of maternal TSH with child total grey matter volume (p
=0·053) and cortical volume (p
=0·086) differed by the duration of gestation. Analyses stratified for gestational age at blood sampling showed an inverted U-shaped association of maternal TSH with child total grey matter volume and cortical grey matter volume, which was most evident at 8 weeks gestation. After about 14 weeks of gestation, TSH was no longer associated with child brain morphology. Maternal FT
concentrations were not associated with child total grey matter volume after adjusting for total intracranial volume (p=0·75).
Here, we show that both low and high maternal thyroid function are associated with smaller child total grey matter and cortical volume. To the best of our knowledge, this study is the first to show that an association with a neurodevelopmental outcome is most evident when maternal thyroid function is measured early in pregnancy. These novel findings suggest that embryonic brain development is particularly vulnerable to altered maternal thyroid function.
Netherlands Organisation for Health Research and Development and the Sophia Children's Hospital Foundation.
Gestational thyroid dysfunction is common and associated with maternal and child morbidity and mortality. During pregnancy, profound changes in thyroid physiology occur, resulting in different ...thyroid-stimulating hormone (TSH) and free thyroxine (FT4) reference intervals compared to the nonpregnant state. Therefore, international guidelines recommend calculating trimester- and assay-specific reference intervals per center. If these reference intervals are unavailable, TSH reference intervals of 0.1-2.5 mU/L for the first trimester and 0.2-3.0 mU/L for the second trimester are recommended. In daily practice, most institutions do not calculate institution-specific reference intervals but rely on these fixed reference intervals for the diagnosis and treatment of thyroid disorders during pregnancy. However, the calculated reference intervals for several additional pregnancy cohorts have been published in the last few years and show substantial variation.
We provide a detailed overview of the available studies on thyroid function reference intervals during pregnancy, different factors that contribute to these reference intervals, and the maternal and child complications associated with only minor variations in thyroid function.
There are large differences in thyroid function reference intervals between different populations of pregnant women. These differences can be explained by variations in assays as well as population-specific factors, such as ethnicity and body mass index. The importance of using correct reference intervals is underlined by the fact that even small subclinical variations in thyroid function have been associated with detrimental pregnancy outcomes, including low birth weight and pregnancy loss. It is therefore crucial that institutions do not rely on fixed universal cutoff concentrations, but calculate their own pregnancy-specific reference intervals.
Summary
Exposure to maternal hypothyroxinemia during pregnancy, which is characterized by low free T4 but normal thyroid‐stimulating hormone (TSH) levels, can negatively affect the foetus. This ...review provides an overview of present findings concerning the association between maternal hypothyroxinemia during pregnancy and childhood cognitive functioning. Possible causes of maternal hypothyroxinemia and potential mechanisms underlying this association are also discussed. Clinical and epidemiological studies suggest that maternal hypothyroxinemia in the first half of pregnancy but not later in pregnancy impairs cognitive development in infancy and childhood. Animal models confirm that the first half of pregnancy may constitute a sensitive period in which maternal hypothyroxinemia alters neurogenesis and causes neuronal migration errors in the developing foetal brain. However, observational studies in humans cannot demonstrate causality of the association between hypothyroxinemia and neurodevelopment. In the only completed randomized trial of antenatal thyroid screening and subsequent levothyroxine treatment of mild maternal subclinical thyroid dysfunction, including hypothyroxinemia, the interventions did not affect offspring intelligence quotient (IQ). More randomized trials are needed investigating whether screening for hypothyroxinemia and its treatment earlier in the first trimester of pregnancy can improve child cognitive functioning or prevent neurodevelopmental changes. Long‐term observational studies should identify molecular, neuroanatomical and neurophysiological factors involved in the association between maternal hypothyroxinemia and offspring cognitive functioning. Information on such mechanisms can be used for the development of innovative prevention and intervention studies that address maternal hypothyroxinemia and its potential consequences.
Thyroid hormone (TH) is crucial for development and metabolism of many tissues. The physiological relevance and therapeutic potential of TH analogs have gained attention in the field for many years. ...In particular, the relevance and use of 3,3',5-triiodothyroacetic acid (Triac, TA
) has been explored over the last decades. Although TA
closely resembles the bioactive hormone T
, differences in transmembrane transport and receptor isoform-specific transcriptional activation potency exist. For these reasons, the application of TA
as a treatment for resistance to TH (RTH) syndromes, especially MCT8 deficiency, is topic of ongoing research. This review is a summary of all currently available literature about the formation, metabolism, action and therapeutic applications of TA
.
For a long time it has been known that both hypo- and hyperthyroidism are associated with an increased risk of morbidity and mortality. In recent years, it has also become clear that minor variations ...in thyroid function, including subclinical dysfunction and variation in thyroid function within the reference range, can have important effects on clinical endpoints, such as bone mineral density, depression, metabolic syndrome, and cardiovascular mortality. Serum thyroid parameters show substantial interindividual variability, whereas the intraindividual variability lies within a narrow range. This suggests that every individual has a unique hypothalamus-pituitary-thyroid axis setpoint that is mainly determined by genetic factors, and this heritability has been estimated to be 40–60%. Various mutations in thyroid hormone pathway genes have been identified in persons with thyroid dysfunction or altered thyroid function tests. Because these causes are rare, many candidate gene and linkage studies have been performed over the years to identify more common variants (polymorphisms) associated with thyroid (dys)function, but only a limited number of consistent associations have been found. However, in the past 5 years, advances in genetic research have led to the identification of a large number of new candidate genes. In this review, we provide an overview of the current knowledge about the polygenic basis of thyroid (dys)function. This includes new candidate genes identified by genome-wide approaches, what insights these genes provide into the genetic basis of thyroid (dys)function, and which new techniques will help to further decipher the genetic basis of thyroid (dys)function in the near future.
Hyperthyroidism Chaker, Layal; Cooper, David S; Walsh, John P ...
The Lancet (British edition),
02/2024, Volume:
403, Issue:
10428
Journal Article
Peer reviewed
Thyrotoxicosis causes a variety of symptoms and adverse health outcomes. Hyperthyroidism refers to increased thyroid hormone synthesis and secretion, most commonly from Graves' disease or toxic ...nodular goitre, whereas thyroiditis (typically autoimmune, viral, or drug induced) causes thyrotoxicosis without hyperthyroidism. The diagnosis is based on suppressed serum concentrations of thyroid-stimulating hormone (TSH), accompanied by free thyroxine and total or free tri-iodothyronine concentrations, which are raised (overt hyperthyroidism) or within range (subclinical hyperthyroidism). The underlying cause is determined by clinical assessment, detection of TSH-receptor antibodies and, if necessary, radionuclide thyroid scintigraphy. Treatment options for hyperthyroidism include antithyroid drugs, radioactive iodine, and thyroidectomy, whereas thyroiditis is managed symptomatically or with glucocorticoid therapy. In Graves' disease, first-line treatment is a 12–18-month course of antithyroid drugs, whereas for goitre, radioactive iodine or surgery are preferred for toxic nodules or goitres. Evidence also supports long-term treatment with antithyroid drugs as an option for patients with Graves' disease and toxic nodular goitre.
In clinical guidelines, overt and subclinical thyroid dysfunction are mentioned as causal and treatable factors for cognitive decline. However, the scientific literature on these associations shows ...inconsistent findings.
To assess cross-sectional and longitudinal associations of baseline thyroid dysfunction with cognitive function and dementia.
This multicohort individual participant data analysis assessed 114 267 person-years (median, 1.7-11.3 years) of follow-up for cognitive function and 525 222 person-years (median, 3.8-15.3 years) for dementia between 1989 and 2017. Analyses on cognitive function included 21 cohorts comprising 38 144 participants. Analyses on dementia included eight cohorts with a total of 2033 cases with dementia and 44 573 controls. Data analysis was performed from December 2016 to January 2021.
Thyroid function was classified as overt hyperthyroidism, subclinical hyperthyroidism, euthyroidism, subclinical hypothyroidism, and overt hypothyroidism based on uniform thyrotropin cutoff values and study-specific free thyroxine values.
The primary outcome was global cognitive function, mostly measured using the Mini-Mental State Examination. Executive function, memory, and dementia were secondary outcomes. Analyses were first performed at study level using multivariable linear regression and multivariable Cox regression, respectively. The studies were combined with restricted maximum likelihood meta-analysis. To overcome the use of different scales, results were transformed to standardized mean differences. For incident dementia, hazard ratios were calculated.
Among 74 565 total participants, 66 567 (89.3%) participants had normal thyroid function, 577 (0.8%) had overt hyperthyroidism, 2557 (3.4%) had subclinical hyperthyroidism, 4167 (5.6%) had subclinical hypothyroidism, and 697 (0.9%) had overt hypothyroidism. The study-specific median age at baseline varied from 57 to 93 years; 42 847 (57.5%) participants were women. Thyroid dysfunction was not associated with global cognitive function; the largest differences were observed between overt hypothyroidism and euthyroidism-cross-sectionally (-0.06 standardized mean difference in score; 95% CI, -0.20 to 0.08; P = .40) and longitudinally (0.11 standardized mean difference higher decline per year; 95% CI, -0.01 to 0.23; P = .09). No consistent associations were observed between thyroid dysfunction and executive function, memory, or risk of dementia.
In this individual participant data analysis of more than 74 000 adults, subclinical hypothyroidism and hyperthyroidism were not associated with cognitive function, cognitive decline, or incident dementia. No rigorous conclusions can be drawn regarding the role of overt thyroid dysfunction in risk of dementia. These findings do not support the practice of screening for subclinical thyroid dysfunction in the context of cognitive decline in older adults as recommended in current guidelines.
During the Coronavirus Disease 2019 (COVID-19) pandemic, the number of consultations and diagnoses in primary care and referrals to specialist care declined substantially compared to prepandemic ...levels. Beyond deferral of elective non-COVID-19 care by healthcare providers, it is unclear to what extent healthcare avoidance by community-dwelling individuals contributed to this decline in routine healthcare utilisation. Moreover, it is uncertain which specific symptoms were left unheeded by patients and which determinants predispose to healthcare avoidance in the general population. In this cross-sectional study, we assessed prevalence of healthcare avoidance during the pandemic from a patient perspective, including symptoms that were left unheeded, as well as determinants of healthcare avoidance.
On April 20, 2020, a paper COVID-19 survey addressing healthcare utilisation, socioeconomic factors, mental and physical health, medication use, and COVID-19-specific symptoms was sent out to 8,732 participants from the population-based Rotterdam Study (response rate 73%). All questionnaires were returned before July 10, 2020. By hand, prevalence of healthcare avoidance was subsequently verified through free text analysis of medical records of general practitioners. Odds ratios (ORs) for avoidance were determined using logistic regression models, adjusted for age, sex, and history of chronic diseases. We found that 1,142 of 5,656 included participants (20.2%) reported having avoided healthcare. Of those, 414 participants (36.3%) reported symptoms that potentially warranted urgent evaluation, including limb weakness (13.6%), palpitations (10.8%), and chest pain (10.2%). Determinants related to avoidance were older age (adjusted OR 1.14 95% confidence interval (CI) 1.08 to 1.21), female sex (1.58 1.38 to 1.82), low educational level (primary education versus higher vocational/university 1.21 1.01 to 1.46), poor self-appreciated health (per level decrease 2.00 1.80 to 2.22), unemployment (versus employed 2.29 1.54 to 3.39), smoking (1.34 1.08 to 1.65), concern about contracting COVID-19 (per level increase 1.28 1.19 to 1.38) and symptoms of depression (per point increase 1.13 1.11 to 1.14) and anxiety (per point increase 1.16 1.14 to 1.18). Study limitations included uncertainty about (perceived) severity of the reported symptoms and potentially limited generalisability given the ethnically homogeneous study population.
In this population-based cross-sectional study, 1 in 5 individuals avoided healthcare during lockdown in the COVID-19 pandemic, often for potentially urgent symptoms. Healthcare avoidance was strongly associated with female sex, fragile self-appreciated health, and high levels of depression and anxiety. These results emphasise the need for targeted public education urging these vulnerable patients to timely seek medical care for their symptoms to mitigate major health consequences.
Summary
Thyroid hormone is an important regulator of early brain development, particularly during early stages of gestation during which foetal thyroid hormone availability depends on the maternal ...transfer of thyroid hormones. There is a wide range of experimental studies showing that low maternal thyroid hormone availability is associated with suboptimal brain development parameters. While few clinical studies have shown that overt maternal hypothyroidism is associated with lower child IQ, the question whether more subclinical changes in maternal thyroid function could also lead to suboptimal foetal brain development. In this review, we put the latter studies in perspective and discuss their interpretation from an epidemiological and clinical perspective. Furthermore, we extend this discussion to also include future perspective and identify important knowledge gaps in the field.
An up-to-date overview of determinants of serum immunoglobulins in adults is pivotal for clinical practice and research, but currently lacking. We therefore performed a systematic review and ...meta-analysis to identify determinants of serum immunoglobulin levels.
Embase, Web of Science, Medline, Cochrane, and Google Scholar were searched from inception to July 11
, 2019 for articles reporting on determinants of serum immunoglobulin A, G or M (IgA, IgG or IgM) in adult humans. Random and fixed effect models were applied to obtain pooled mean differences (MDs) and 95% confidence intervals (CIs) for the association of age and sex with serum immunoglobulins.
We retrieved 117 articles reporting on determinants of serum immunoglobulins, of which 28 could be meta-analyzed. Older compared to younger individuals had higher IgA (MD: 0.38; CI: 0.18 - 0.58), but lower IgM levels (MD: -0.40; 95%: -0.66 - -0.14). Men had higher IgA (MD: 0.22; CI: 0.03 - 0.42), but lower IgM levels (MD: -0.21; CI: -0.32 - -0.10) than women. Age and sex did not influence IgG. Caucasian ethnicity was associated with lower IgA, IgG, and IgM. Smoking and corticosteroid use were associated with lower IgG. Positive associations were reported of probiotics with IgG, alcohol with IgA, hypertension with IgA and IgG, and acute psychological stress with IgA, IgG, and IgM.
Older age and male sex are associated with higher IgA, but lower IgM, and urge investigation of age- and sex-specific reference ranges of immunoglobulins. Other identified determinants were ethnicity, diet, lifestyle and cardio-metabolic factors.
PDF
