Exploration of thyroglobulin as a biomarker of iodine status in iodine-sufficient and mildly iodine-deficient pregnant women.

PURPOSE: Urinary iodine-to-creatinine ratio (UI/Creat) reflects recent iodine intake but has limitations for assessing habitual intake. Thyroglobulin (Tg) concentration, which increases with thyroid size, appears to be an indicator of longer-term iodine status in children and adults, however, less is known in pregnancy. This study investigated the determinants of serum-Tg in pregnancy and its use as an iodine-status biomarker in settings of iodine-sufficiency and mild-to-moderate deficiency. METHODS: Stored blood samples and existing data from pregnant women from the Netherlands-based Generation R (iodine-sufficient) and the Spain-based INMA (mildly-to-moderately iodine-deficient) cohorts were used. Serum-Tg and iodine status (as spot-urine UI/Creat) were measured at median 13 gestational weeks. Using regression models, maternal socio-demographics, diet and iodine-supplement use were investigated as determinants of serum-Tg, as well as the association between UI/Creat and serum-Tg. RESULTS: Median serum-Tg was 11.1 ng/ml in Generation R (n = 3548) and 11.5 ng/ml in INMA (n = 1168). When using 150 µg/g threshold for iodine deficiency, serum-Tg was higher in women with UI/Creat < 150 vs ≥ 150 µg/g (Generation R, 12.0 vs 10.4 ng/ml, P = 0.010; INMA, 12.8 vs 10.4 ng/ml, P < 0.001); after confounder adjustment, serum-Tg was still higher when UI/Creat < 150 µg/g (regression coefficients: Generation R, B = 0.111, P = 0.050; INMA, B = 0.157, P = 0.010). Iodine-supplement use and milk intake were negatively associated with serum-Tg, whereas smoking was positively associated. CONCLUSION: The association between iodine status and serum-Tg was stronger in the iodine-deficient cohort, than in the iodine-sufficient cohort. Serum-Tg might be a complementary (to UI/Creat) biomarker of iodine status in pregnancy but further evidence is needed.

Associations Between Prenatal Exposure to Air Pollution and Congenital Hypothyroidism.

Adequate thyroid hormone availability is required for normal brain development. Studies have found associations between prenatal exposure to air pollutants and thyroid hormones in pregnant women and newborns. We aimed to examine associations of trimester-specific residential exposure to common air pollutants with congenital hypothyroidism (CHT). All term infants born in Israel during 2009-2015 were eligible for inclusion. We used data on CHT from the national neonatal screening lab of Israel, and exposure data from spatiotemporal air pollution models. We used multivariable logistic regression models to estimate associations of exposures with CHT, adjusting for ethnicity, socioeconomic status, geographical area, conception season, conception year, gestational age, birth weight, and child sex. To assess residual confounding, we used postnatal exposures to the same pollutants as negative controls. The study population included 696,461 neonates. We found a positive association between third-trimester nitrogen oxide exposure and CHT (per interquartile-range change, odds ratio = 1.23, 95% confidence interval: 1.08, 1.41) and a similar association for nitrogen dioxide. There was no evidence of residual confounding or bias by correlation among exposure periods for these associations.

Maternal Iodine Status During Pregnancy Is Not Consistently Associated with Attention-Deficit Hyperactivity Disorder or Autistic Traits in Children.

BACKGROUND: Severe iodine deficiency during pregnancy can cause intellectual disability, presumably through inadequate placental transfer of maternal thyroid hormone to the fetus. The association between mild-to-moderate iodine deficiency and child neurodevelopmental problems is not well understood. OBJECTIVES: We investigated the association of maternal iodine status during pregnancy with child attention-deficit hyperactivity disorder (ADHD) and autistic traits. METHODS: This was a collaborative study of 3 population-based birth cohorts: Generation R (n = 1634), INfancia y Medio Ambiente (n = 1293), and the Avon Longitudinal Study of Parents and Children (n = 2619). Exclusion criteria were multiple fetuses, fertility treatment, thyroid-interfering medication use, and pre-existing thyroid disease. The mean age of assessment in the cohorts was between 4.4 and 7.7 y for ADHD symptoms and 4.5 and 7.6 y for autistic traits. We studied the association of the urinary iodine-to-creatinine ratio (UI/Creat) <150 µg/g-in all mother-child pairs, and in those with a urinary-iodine measurement at ≤18 weeks and ≤14 weeks of gestation-with the risk of ADHD or a high autistic-trait score (≥93rd percentile cutoff), using logistic regression. The cohort-specific effect estimates were combined by random-effects meta-analyses. We also investigated whether UI/Creat modified the associations of maternal free thyroxine (FT4) or thyroid-stimulating hormone concentrations with ADHD or autistic traits. RESULTS: UI/Creat <150 µg/g was not associated with ADHD (OR: 1.2; 95% CI: 0.7, 2.2; P = 0.56) or with a high autistic-trait score (OR: 0.8; 95% CI: 0.6, 1.1; P = 0.22). UI/Creat <150 µg/g in early pregnancy (i.e., ≤18 weeks or ≤14 weeks of gestation) was not associated with a higher risk of behavioral problems. The association between a higher FT4 and a greater risk of ADHD (OR: 1.3; 95% CI: 1.0, 1.6; P = 0.017) was not modified by iodine status. CONCLUSIONS: There is no consistent evidence to support an association of mild-to-moderate iodine deficiency during pregnancy with child ADHD or autistic traits.

Similarities and differences of dietary and other determinants of iodine status in pregnant women from three European birth cohorts.

PURPOSE: As a component of thyroid hormones, adequate iodine intake is essential during pregnancy for fetal neurodevelopment. Across Europe, iodine deficiency is common in pregnancy, but data are lacking on the predictors of iodine status at this life stage. We, therefore, aimed to explore determinants of iodine status during pregnancy in three European populations of differing iodine status. METHODS: Data were from 6566 pregnant women from three prospective population-based birth cohorts from the United Kingdom (ALSPAC, n = 2852), Spain (INMA, n = 1460), and The Netherlands (Generation R, n = 2254). Urinary iodine-to-creatinine ratio (UI/Creat, µg/g) was measured in spot-urine samples in pregnancy (≤ 18-weeks gestation). Maternal dietary intake, categorised by food groups (g/day), was estimated from food-frequency questionnaires (FFQs). Multivariable regression models used dietary variables (energy-adjusted) and maternal characteristics as predictors of iodine status. RESULTS: Median UI/Creat in pregnant women of ALSPAC, INMA, and Generation R was 121, 151, and 210 µg/g, respectively. Maternal age was positively associated with UI/Creat in all cohorts (P < 0.001), while UI/Creat varied by ethnicity only in Generation R (P < 0.05). Of the dietary predictors, intake of milk and dairy products (per 100 g/day) was positively associated with UI/Creat in all cohorts [ALSPAC (B = 3.73, P < 0.0001); INMA (B = 6.92, P = 0.002); Generation R (B = 2.34, P = 0.001)]. Cohort-specific dietary determinants positively associated with UI/Creat included fish and shellfish in ALSPAC and INMA, and eggs and cereal/cereal products in Generation R. CONCLUSIONS: The cohort-specific dietary determinants probably reflect not only dietary habits but iodine-fortification policies; hence, public-health interventions to improve iodine intake in pregnancy need to be country-specific.

Removing Critical Gaps in Chemical Test Methods by Developing New Assays for the Identification of Thyroid Hormone System-Disrupting Chemicals-The ATHENA Project.

The test methods that currently exist for the identification of thyroid hormone system-disrupting chemicals are woefully inadequate. There are currently no internationally validated in vitro assays, and test methods that can capture the consequences of diminished or enhanced thyroid hormone action on the developing brain are missing entirely. These gaps put the public at risk and risk assessors in a difficult position. Decisions about the status of chemicals as thyroid hormone system disruptors currently are based on inadequate toxicity data. The ATHENA project (Assays for the identification of Thyroid Hormone axis-disrupting chemicals: Elaborating Novel Assessment strategies) has been conceived to address these gaps. The project will develop new test methods for the disruption of thyroid hormone transport across biological barriers such as the blood-brain and blood-placenta barriers. It will also devise methods for the disruption of the downstream effects on the brain. ATHENA will deliver a testing strategy based on those elements of the thyroid hormone system that, when disrupted, could have the greatest impact on diminished or enhanced thyroid hormone action and therefore should be targeted through effective testing. To further enhance the impact of the ATHENA test method developments, the project will develop concepts for better international collaboration and development in the area of thyroid hormone system disruptor identification and regulation.

Clinical associations of maternal thyroid function with foetal brain development: Epidemiological interpretation and overview of available evidence.

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.

Frequent atrial extrasystolic beats predict atrial fibrillation in patients with congenital heart defects.

Aims: Atrial fibrillation (AF) is increasingly observed in patients with congenital heart defects (CHDs) who survive nowadays into adulthood. Yet, predictors of AF are scarce in this high-risk population. This study therefore examined the predictive ability of atrial extrasystole (AES) for development of AF in CHD patients. Methods and results: Adult CHD patients who had a 24 h Holter registration were followed to determine who developed AF. A total of 573 patients (49% male, mean age 35 ± 12 years) were included; they had a simple/complete repaired CHD (n = 279), complex repaired CHD (n = 251), or univentricular heart (UVH, n = 43). Ageing (P < 0.0001), female gender (P = 0.028), UVH (P = 0.0010), and left atrial dilatation (P = 0.0025) were associated with the number of AES. During a median follow-up of 51.6 months (interquartile range 22.8-85.7), 29 patients (5%) developed de novo AF. An one-point increase in the number of logtotal-AES was associated with a two-fold higher risk of AF development (hazard ratio 1.95; 95% confidence interval 1.21-3.13; P = 0.016). C-statistic for left atrial dilatation, complexity, and age had a good discriminative ability for the incidence of AF with a C-statistic of 84.5%. The addition of the total number of AES/24 h to this model increased C-statistic to 88.4%. Conclusion: Atrial extrasystole occur relatively frequent in adult CHD patients compared with patients with other cardiac diseases. This is the first study that showed an association between an increased AES frequency and a higher risk of AF development in CHD patients.

Maternal thyroid function, prepregnancy obesity and gestational weight gain-The Generation R Study: A prospective cohort study.

OBJECTIVE: Maternal prepregnancy obesity and excessive gestational weight gain are associated with pregnancy complications. Thyroid function is related to differences in body mass index (BMI) in adult populations. We examined the associations of maternal thyroid function in early pregnancy with maternal BMI and weight gain during pregnancy. DESIGN AND METHODS: In a population-based prospective cohort study among 5726 mothers, we measured maternal TSH and FT4 levels at 13.5 weeks of gestation (95% range: 9.7-17.6 weeks). Maternal weight was assessed before pregnancy and in each trimester. RESULTS: Higher maternal TSH levels were associated with higher prepregnancy BMI (difference: 0.18 kg/m2 [95% CI: 0.01, 0.36] per SD increase in maternal TSH level) and higher total gestational weight gain (difference: 0.02 kg/wk [95% CI: 0.01, 0.03] per SD increase in maternal TSH level). Higher maternal FT4 levels were associated with lower prepregnancy BMI (difference: -0.44 kg/m2 [95% CI: -0.63, -0.26] per SD increase in maternal FT4 level) and lower total gestational weight gain (difference: -0.01 kg/wk [95% CI: -0.02, -0.01] per SD increase in maternal FT4 level). The associations of maternal thyroid function with weight gain in early pregnancy were stronger than those with weight gain in mid and late-pregnancy. Maternal hypothyroidism was associated with higher prepregnancy BMI and early pregnancy weight gain, whereas opposite effects were observed for maternal hyperthyroidism (P<.05). CONCLUSIONS: Higher maternal TSH level and lower FT4 level in early pregnancy are associated with higher prepregnancy BMI and higher gestational weight gain. Further studies are needed to explore maternal and foetal consequences.

Human chorionic gonadotropin (hCG) concentrations during the late first trimester are associated with fetal growth in a fetal sex-specific manner.

Human chorionic gonadotropin (hCG) is a pregnancy-specific hormone that regulates placental development. hCG concentrations vary widely throughout gestation and differ based on fetal sex. Abnormal hCG concentrations are associated with adverse pregnancy outcomes including fetal growth restriction. We studied the association of hCG concentrations with fetal growth and birth weight. In addition, we investigated effect modification by gestational age of hCG measurement and fetal sex. Total serum hCG (median 14.4 weeks, 95 % range 10.1-26.2), estimated fetal weight (measured by ultrasound during 18-25th weeks and >25th weeks) and birth weight were measured in 7987 mother-child pairs from the Generation R cohort and used to establish fetal growth. Small for gestational age (SGA) was defined as a standardized birth weight lower than the 10th percentile of the study population. There was a non-linear association of hCG with birth weight (P = 0.009). However, only low hCG concentrations measured during the late first trimester (11th and 12th week) were associated with birth weight and SGA. Low hCG concentrations measured in the late first trimester were also associated with decreased fetal growth (P = 0.0002). This was the case for both male and female fetuses. In contrast, high hCG concentrations during the late first trimester were associated with increased fetal growth amongst female, but not male fetuses. Low hCG in the late first trimester is associated with lower birth weight due to a decrease in fetal growth. Fetal sex differences exist in the association of hCG concentrations with fetal growth.

Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease.

Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5×10(-8)) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68-2.81, P = 8.1×10(-8)), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26-1.82, P = 2.9×10(-6)), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66-0.89, P = 6.5×10(-4)). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves' disease (OR: 1.37, 95% CI 1.22-1.54, P = 1.2×10(-7) and OR: 1.25, 95% CI 1.12-1.39, P = 6.2×10(-5)). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18-2.10, P = 1.9×10(-3)). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.

Thyroid function and risk of type 2 diabetes: a population-based prospective cohort study.

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.

Risk factors and a clinical prediction model for low maternal thyroid function during early pregnancy: two population-based prospective cohort studies.

BACKGROUND: Low maternal thyroid function during early pregnancy is associated with various adverse outcomes including impaired neurocognitive development of the offspring, premature delivery and abnormal birthweight. AIM: To aid doctors in the risk assessment of thyroid dysfunction during pregnancy, we set out to investigate clinical risk factors and derive a prediction model based on easily obtainable clinical variables. METHODS: In total, 9767 women during early pregnancy (≤18 week) were selected from two population-based prospective cohorts: the Generation R Study (N = 5985) and the ABCD study (N = 3782). We aimed to investigate the association of easily obtainable clinical subject characteristics such as maternal age, BMI, smoking status, ethnicity, parity and gestational age at blood sampling with the risk of low free thyroxine (FT4) and elevated thyroid stimulating hormone (TSH), determined according to the 2·5th-97·5th reference range in TPOAb negative women. RESULTS: BMI, nonsmoking and ethnicity were risk factors for elevated TSH levels; however, the discriminative ability was poor (range c-statistic of 0·57-0·60). Sensitivity analysis showed that addition of TPOAbs to the model yielded a c-statistic of 0·73-0·75. Maternal age, BMI, smoking, parity and gestational age at blood sampling were risk factors for low FT4, which taken together provided adequate discrimination (range c-statistic of 0·72-0·76). CONCLUSIONS: Elevated TSH levels depend predominantly on TPOAb levels, and prediction of elevated TSH levels is not possible with clinical characteristics only. In contrast, the validated clinical prediction model for FT4 had high discriminative value to assess the likelihood of low FT4 levels.

Maternal total T4 during the first half of pregnancy: physiologic aspects and the risk of adverse outcomes in comparison with free T4.

AIM: We aimed to investigate TT4 physiological aspects and associations with clinical end-points. BACKGROUND: Total T4 (TT4) has been suggested as a marker for maternal thyroid function during pregnancy because as compared to FT4 (i) TT4 measurement is not affected by binding protein interference, (ii) TT4 is considered to be more stable from the second trimester onwards, and (iii) TT4 better reflects changes in the hypothalamic-pituitary-thyroid axis. However, this is based on data from small studies, and, more importantly, it is unknown whether TT4 is associated with adverse pregnancy or child outcomes. METHODS: We selected 5647 mother-child pairs from a large population-based prospective cohort with data on maternal TSH, FT4 and TT4 during early pregnancy (median 13·2 weeks, 95% range 9·8-17·6). We used multivariable (non)linear and logistic regression models to study the association of maternal TT4 with pre-eclampsia, premature delivery, birthweight and offspring IQ and compare the results with previously obtained results for FT4. RESULTS: The change of mean TT4 levels was 27·5% compared to 20·2% for FT4. There was a log-linear association of TT4 and FT4 with TSH, but the explained variability of TSH was much lower for TT4 than for FT4 (R-squared TT4: 2·5% vs 8·0% for FT4). In contrast to FT4, there was no independent association of maternal TT4 with pre-eclampsia, premature delivery, birthweight or offspring IQ. CONCLUSION: Maternal TT4 levels are highly variable in the first half of pregnancy and are poorly related to maternal TSH. This study shows that maternal TT4 levels are either not associated, or not better associated as compared to FT4, with adverse pregnancy or child outcomes. This suggests that the maternal TT4 is inferior to FT4 in the assessment of maternal thyroid function during the first half of pregnancy.

Thyroid function in pregnancy: what is normal?

BACKGROUND: 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. CONTENT: 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. SUMMARY: 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.

Reference ranges and determinants of total hCG levels during pregnancy: the Generation R Study.

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.

Maternal thyroid hormones during pregnancy, childhood adiposity and cardiovascular risk factors: the Generation R Study.

OBJECTIVE: Variation in maternal thyroid function during early pregnancy may permanently affect childhood growth and cardiovascular development. We examined the associations of early pregnancy maternal TSH and free T4 (FT4) levels with childhood growth, body composition and cardiovascular characteristics. METHODS: We performed a population-based prospective cohort study among 5646 mothers and their children. Maternal thyroid parameters were assessed in early pregnancy (median: 13·2 weeks; 95% range: 9·7-17·6 weeks). Childhood growth was repeatedly measured from birth to 6 years. At the age of 6 years, childhood body mass index (BMI), total body and abdominal fat distribution, blood pressure and left ventricular mass were measured. RESULTS: Maternal thyroid parameters were not consistently associated with childhood length and weight growth characteristics. Lower maternal TSH levels were associated with lower childhood BMI, total fat mass, abdominal subcutaneous fat mass area and diastolic blood pressure (P-values <0·05), but not with preperitoneal abdominal fat mass area, systolic blood pressure or left ventricular mass. Higher maternal FT4 levels were associated with lower childhood BMI, abdominal subcutaneous and preperitoneal fat mass area (P for trends <0·05), but not with other cardiovascular characteristics. Clinically maternal hypothyroid or hyperthyroid statuses were not associated with childhood growth, body fat or cardiovascular outcomes. CONCLUSIONS: Maternal thyroid function during early pregnancy may influence childhood body composition and cardiovascular development. Further studies are needed to replicate these findings and to examine the influence of maternal thyroid hormone levels during pregnancy on long-term growth and cardiovascular development in the offspring.

Association of maternal thyroglobulin with gestational thyroid function and offspring IQ and brain morphology.

BACKGROUND: Low maternal urinary iodine concentration (UIC) during pregnancy is associated with adverse offspring neurodevelopment. Thyroglobulin (Tg) has been suggested as a more sensitive biomarker than UIC of long-term iodine status, but associations of Tg with neurodevelopment and the possible mediating role of thyroid function remain unknown. AIM: To study whether maternal Tg is associated with i) maternal and newborn thyroid function and ii) offspring IQ and brain morphology. METHODS: Participants were selected from two population-based prospective cohorts: Generation R (the Netherlands, iodine-sufficient) and INfancia y Medio Ambiente (Spain, mildly iodine-deficient) with maternal Tg and thyroid function data in the first half of pregnancy or in cord blood, early childhood IQ (age 4.5 and 6 years), late childhood IQ (age 9 and 13), or brain morphology at 10 years. Associations of Tg with TSH, FT4, IQ and brain morphology were studied with multivariable linear regression. RESULTS: i) Tg was associated with lower TSH (-0.12[-0.16; -0.08]) and higher FT4 (0.08[0.05;0.12]) in pregnancy (N=4,367), but not with cord blood TSH or FT4 (N=2,008). ii) Tg was associated with lower IQ in early childhood (ß[95% CI]:-0.06 [-0.10; -0.01], N=2,919), but not with IQ (N=2,503) or brain morphology (N=1,180) in later childhood. None of the associations of Tg with the studied outcomes differed by the iodine-to-creatinine ratio (i.e. effect modification) or changed when adjusted for thyroid function. CONCLUSIONS: Higher Tg is associated with lower IQ in early childhood and higher thyroid function during pregnancy, but not with IQ or brain morphology in later childhood. Further research should determine the value of Tg in addition to UIC for defining iodine status.

Iodineminho Study: Iodine Supplementation and Prevalence of Iodine Deficiency In Pregnant Women.

CONTEXT: Iodine is necessary for proper brain development. The prevalence of iodine deficiency in Portuguese pregnant women led the health authorities, in 2013, to recommend iodine supplementation for women in preconception, throughout pregnancy, and during lactation. OBJECTIVE: This work aimed to assess the effect of iodine supplementation initiated in the preconception or the first trimester of pregnancy on the prevalence of iodine deficiency and maternal thyroid status. METHODS: An observational prospective cohort study was conducted that followed the thyroid function and iodine status of women recruited during preconception or in the first trimester of pregnancy. RESULTS: Median urinary iodine concentration (UIC) was significantly higher among women taking iodine supplements (no-supplement group UIC = 63 µg/L; supplement group UIC = 100 µg/L; P = .002) but still below the levels recommended by the World Health Organization. Only 15% of pregnant women had adequate iodine status and 17% showed a UIC of less than 50 µg/L. There was no influence whether iodine supplementation was started during preconception or during the first trimester of gestation (UIC preconception group: 112 µg/L vs UIC pregnancy group: 91 µg/L; P = .569). In the first trimester of pregnancy, total thyroxine levels were lower and free triiodothyronine levels were higher in nonsupplemented women. Thyroglobulin levels were lower in women who started iodine supplementation during preconception compared to nonsupplemented women and women who started iodine supplementation during gestation. CONCLUSION: In the Minho region of Portugal, fertile women have insufficient iodine intake. Additional public health measures are needed since the current recommendations for iodine supplementation for pregnancy are unsatisfactory to achieve adequate iodine status.

Predictors of treatment response in lymphogenic metastasized papillary thyroid cancer: a histopathological study.

BACKGROUND: Lymph node metastases in papillary thyroid cancer (PTC) increase the risk for persistent and recurrent disease. Data on the predictive value of histopathological features of lymph node metastases, however, are inconsistent. The aim of this study was to evaluate the prognostic significance of known and new histopathological features of lymph node metastases in a well-defined cohort of PTC patients with clinically evident lymph node metastases. METHODS: A total of 1042 lymph node metastases, derived from 129 PTC patients, were reexamined according to a predefined protocol and evaluated for diameter, extranodal extension, cystic changes, necrosis, calcifications, and the proportion of the lymph node taken up by tumor cells. Predictors for a failure to achieve a complete biochemical and structural response to treatment were determined. RESULTS: The presence of more than 5 lymph node metastases was the only independent predictor for a failure to achieve a complete response to treatment (odds ratio [OR] 3.39 [95% CI, 1.57-7.33], P < .05). Diameter nor any of the other evaluated lymph node features were significantly associated with the response to treatment. CONCLUSIONS: Detailed reexamination of lymph nodes revealed that only the presence of more than 5 lymph node metastases was an independent predictor of failure to achieve a complete response to treatment. No predictive value was found for other histopathological features, including the diameter of the lymph node metastases. These findings have the potential to improve risk stratification in patients with PTC and clinically evident lymph node metastases.