Context:
Although both overt hyper- and hypothyroidism are known to lead to cognitive impairment, data on the association between subclinical thyroid dysfunction and cognitive function are ...conflicting.
Objective:
This study sought to determine the risk of dementia and cognitive decline associated with subclinical thyroid dysfunction among prospective cohorts.
Data Sources:
We searched in MEDLINE and EMBASE from inception until November 2014.
Study Selection:
Two physicians identified prospective cohorts that assessed thyroid function and cognitive outcomes (dementia; Mini-Mental State Examination MMSE).
Data Extraction:
Data were extracted by one reviewer following standardized protocols and verified by a second reviewer. The primary outcome was dementia and decline in cognitive function was the secondary outcome.
Data Synthesis:
Eleven prospective cohorts followed 16,805 participants during a median followup of 44.4 months. Five studies analyzed the risk of dementia in subclinical hyperthyroidism (SHyper) (n = 6410), six in subclinical hypothyroidism (SHypo) (n = 7401). Five studies analyzed MMSE decline in SHyper (n = 7895), seven in SHypo (n = 8960). In random-effects models, the pooled adjusted risk ratio for dementia in SHyper was 1.67 (95% confidence interval, 1.04; 2.69) and 1.14 (95% confidence interval, 0.84; 1.55) in SHypo vs euthyroidism, both without evidence of significant heterogeneity (I2 = 0.0%). The pooled mean MMSE decline from baseline to followup (mean 32 mo) did not significantly differ between SHyper or SHypo vs euthyroidism.
Conclusions:
SHyper might be associated with an elevated risk for dementia, whereas SHypo is not, and both conditions are not associated with faster decline in MMSE over time. Available data are limited, and additional large, high-quality studies are needed.
This meta-analysis determined the risk of dementia and cognitive decline associated with subclinical thyroid dysfunction and found a possible association for subclinical hyperthyroidism and dementia.
Interpretation of thyroid function tests during pregnancy Visser, W. Edward; Peeters, Robin P.
Best Practice & Research Clinical Endocrinology & Metabolism,
July 2020, 2020-07-00, 20200701, Letnik:
34, Številka:
4
Journal Article
Recenzirano
Thyroid hormones are crucial for normal pregnancy and fetal development. Large physiological changes occur during pregnancy, posing challenges for the correct interpretation of thyroid function ...tests. TSH concentrations are the principal first test to rule out thyroid disease taking into account trimester-specific reference ranges. Free T4 (FT4) measurements by immuno-assays may be subject to interference by endogenous and exogenous factors. The relevance of measuring free T3 (FT3) during pregnancy is unclear. Thyroid autoimmunity is well-reflected by the presence of antibodies against TPO. TPO-antibody positivity is associated with an increased risk of adverse pregnancy outcomes.
Genetic factors are major determinants of thyroid function. Over the last two decades, multiple genetic variants have been associated with variations in normal range thyroid function tests. Most ...recently, a large-scale genome-wide association study (GWAS) doubled the number of known variants associated with normal range thyrotropin (TSH) and free thyroxine (FT4) levels.
This review summarizes the results of genetic association studies on normal range thyroid function and explores how these genetic variants can be used in future studies to improve our understanding of thyroid hormone regulation and disease.
Serum TSH and FT4 levels are determined by multiple genetic variants on virtually all levels of the hypothalamus-pituitary-thyroid (HPT) axis. Functional follow-up studies on top of GWAS hits has the potential to discover new key players in thyroid hormone regulation, as exemplified by the identification of the thyroid hormone transporter SLC17A4 and the metabolizing enzyme AADAT. Translational studies may use these genetic variants to investigate causal associations between thyroid function and various outcomes in Mendelian Randomization (MR) studies, to identify individuals with an increased risk of thyroid dysfunction, and to predict the individual HPT axis setpoint.
Recent genetic studies have greatly improved our understanding of the genetic basis of thyroid function, and have revealed novel pathways involved in its regulation. In addition, these findings have paved the way for various lines of research that can improve our understanding of thyroid hormone regulation and thyroid diseases, as well as the potential use of these markers in future clinical practice.
Thyroid hormone is involved in the regulation of early brain development. Since the fetal thyroid gland is not fully functional until week 18-20 of pregnancy, neuronal migration and other crucial ...early stages of intrauterine brain development largely depend on the supply of maternal thyroid hormone. Current clinical practice mostly focuses on preventing the negative consequences of low thyroid hormone concentrations, but data from animal studies have shown that both low and high concentrations of thyroid hormone have negative effects on offspring brain development. We aimed to investigate the association of maternal thyroid function with child intelligence quotient (IQ) and brain morphology.
In this population-based prospective cohort study, embedded within the Generation R Study (Rotterdam, Netherlands), we investigated the association of maternal thyroid function with child IQ (assessed by non-verbal intelligence tests) and brain morphology (assessed on brain MRI scans). Eligible women were those living in the study area at their delivery date, which had to be between April 1, 2002, and Jan 1, 2006. For this study, women with available serum samples who presented in early pregnancy (<18 weeks) were included. Data for maternal thyroid-stimulating hormone, free thyroxine, thyroid peroxidase antibodies (at weeks 9-18 of pregnancy), and child IQ (assessed at a median of 6·0 years of age 95% range 5·6-7·9 years) or brain MRI scans (done at a median of 8·0 years of age 6·2-10·0) were obtained. Analyses were adjusted for potential confounders including concentrations of human chorionic gonadotropin and child thyroid-stimulating hormone and free thyroxine.
Data for child IQ were available for 3839 mother-child pairs, and MRI scans were available from 646 children. Maternal free thyroxine concentrations showed an inverted U-shaped association with child IQ (p=0·0044), child grey matter volume (p=0·0062), and cortex volume (p=0·0011). For both low and high maternal free thyroxine concentrations, this association corresponded to a 1·4-3·8 points reduction in mean child IQ. Maternal thyroid-stimulating hormone was not associated with child IQ or brain morphology. All associations remained similar after the exclusion of women with overt hypothyroidism and overt hyperthyroidism, and after adjustment for concentrations of human chorionic gonadotropin, child thyroid-stimulating hormone and free thyroxine or thyroid peroxidase antibodies (continuous or positivity).
Both low and high maternal free thyroxine concentrations during pregnancy were associated with lower child IQ and lower grey matter and cortex volume. The association between high maternal free thyroxine and low child IQ suggests that levothyroxine therapy during pregnancy, which is often initiated in women with subclinical hypothyroidism during pregnancy, might carry the potential risk of adverse child neurodevelopment outcomes when the aim of treatment is to achieve high-normal thyroid function test results.
The Netherlands Organisation for Health Research and Development (ZonMw) and the European Community's Seventh Framework Programme.
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.
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.
To study if maternal thyroid function test abnormalities and thyroid autoimmunity are risk factors for preterm birth.
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.
The primary authors provided individual participant data that were analyzed using mixed-effects models.
The primary outcome was preterm birth (<37 weeks' gestational age).
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).
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.
Atrial fibrillation (AF) is a highly prevalent disorder leading to heart failure, stroke, and death. Enhanced understanding of modifiable risk factors may yield opportunities for prevention. The risk ...of AF is increased in subclinical hyperthyroidism, but it is uncertain whether variations in thyroid function within the normal range or subclinical hypothyroidism are also associated with AF.
We conducted a systematic review and obtained individual participant data from prospective cohort studies that measured thyroid function at baseline and assessed incident AF. Studies were identified from MEDLINE and EMBASE databases from inception to July 27, 2016. The euthyroid state was defined as thyroid-stimulating hormone (TSH) 0.45 to 4.49 mIU/L, and subclinical hypothyroidism as TSH 4.5 to 19.9 mIU/L with free thyroxine (fT4) levels within reference range. The association of TSH levels in the euthyroid and subclinical hypothyroid range with incident AF was examined by using Cox proportional hazards models. In euthyroid participants, we additionally examined the association between fT4 levels and incident AF.
Of 30 085 participants from 11 cohorts (278 955 person-years of follow-up), 1958 (6.5%) had subclinical hypothyroidism and 2574 individuals (8.6%) developed AF during follow-up. TSH at baseline was not significantly associated with incident AF in euthyroid participants or those with subclinical hypothyroidism. Higher fT4 levels at baseline in euthyroid individuals were associated with increased AF risk in age- and sex-adjusted analyses (hazard ratio, 1.45; 95% confidence interval, 1.26-1.66, for the highest quartile versus the lowest quartile of fT4;
for trend ≤0.001 across quartiles). Estimates did not substantially differ after further adjustment for preexisting cardiovascular disease.
In euthyroid individuals, higher circulating fT4 levels, but not TSH levels, are associated with increased risk of incident AF.
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.
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.
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.
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.
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.
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.
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