Isolated maternal hypothyroxinemia (IMH) during pregnancy is defined as a low maternal T
in the absence of TSH elevation. As IMH is common, with a prevalence of 1-2% in iodine-sufficient populations, ...and early research has suggested adverse effects on fetal neurodevelopment, it has been the focus of many studies in the last decade. In the current review, we first discuss the significance of IMH based on data from animal models and recent discoveries regarding the role of thyroid hormone on neurodevelopment. We address issues surrounding the definition and prevalence of this entity and discuss new insights into the etiologies, clinical consequences and management of IMH. A number of large cohort studies have investigated the effects of IMH on the risk of various pregnancy complications and child neurodevelopment. We review these studies in detail and describe their limitations. We discuss the available research on management of IMH, including two recent randomized controlled trials (RCTs). Finally, we delineate the remaining uncertainties in this field and emphasize the need for a sufficiently powered, placebo-controlled RCT on the treatment of IMH early in the first trimester of pregnancy.
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.
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.
Background:
Intrauterine adaptation to the outside environment is an important mechanism via which the fetus increases its chance to thrive after birth. Therefore, various maternal-, pregnancy-, and ...labor-related factors are potential determinants of thyroid function of the offspring. Animal studies suggest that very high maternal thyroid hormone levels during pregnancy can alter the development of the hypothalamic-pituitary-thyroid axis set point of the child. However, to what extent maternal and birth characteristics (including maternal thyroid function, smoking, and birth weight) are associated with thyroid function of the offspring is currently unknown.
Methods:
We selected 4273 mother-child pairs from a large population-based prospective cohort with data available on maternal gestational TSH and free T4 (FT4) levels and newborn TSH and FT4 (n = 3339; at birth) or childhood TSH and FT4 (n = 2523; median age, 6 y). We used multivariable (non)linear regression models to study the association of potential determinants (including maternal TSH, FT4, thyroid peroxidase antibodies, iodine excretion, age, body mass index, smoking status, parity, pre-eclampsia, fetal distress, gestational age at birth, birth weight, mode of delivery, and thyroid function-associated single nucleotide polymorphisms) with newborn and childhood TSH and FT4.
Results:
There was a strong association of maternal TSH and FT4 levels during pregnancy with newborn and childhood TSH and FT4 levels, respectively (for both, P < .0001). Maternal FT4 was also associated with newborn TSH levels (P = .0009). Birth weight, fetal distress, gestational age at birth and maternal parity were all associated with newborn TSH and/or FT4 (P < .0001), but these associations did not persist into childhood. Genetic risk scores for TSH and FT4 were strongly associated with newborn and childhood thyroid function (P ≤ .0005). The association between maternal and offspring thyroid function did not change after correction for genetic risk scores.
Conclusions:
In this study, childhood thyroid function was predominantly determined by maternal TSH or FT4 levels and thyroid-specific single nucleotide polymorphisms. Effects of stress-related changes in thyroid function at birth were transient. Other potential factors were not associated with offspring thyroid function.
Context:
Overt hypo- and hyperthyroidism are associated with an increased risk of depression. Little is known about the effects of variation in thyroid function within the normal range on the risk of ...depression.
Objective:
The objective of the study was to examine the association between normal-range thyroid function and the risk of depression.
Design, Setting, and Participants:
This was a cohort study in 1503 Dutch men and women, aged 70.6 (7.3) (mean SD) years. At baseline, serum TSH, thyroperoxidase antibody levels, and depressive symptoms Center for Epidemiologic Studies Depression Scale (CES-D) were assessed. A CES-D of 16 or greater is indicative of a depressive disorder. During follow-up (mean 8.0 y), participants were continuously monitored for the occurrence of incident depressive syndromes (n = 156).
Results:
Cross-sectionally, persons in the lowest TSH tertile (0.3–1.0 mU/L) had more depressive symptoms CES-D score (mean): 7.95 vs 6.63, P = .014 as well as an increased risk of a CES-D of 16 or greater 10.7% vs 5.0%, odds ratio (95% confidence interval) 2.22 (1.18–4.17), compared with persons in the highest normal range TSH tertile (1.6–4.0 mU/L). In the prospective analyses, persons in the lowest TSH tertile who were depression free at baseline had a higher risk of incident depressive syndromes 12.3% vs 7.6%, odds ratio (95% confidence interval) 1.85 (1.10–3.11). Thyroid autoimmunity (thyroperoxidase antibody positivity) was not associated with CES-D scores or incident depressive syndromes.
Conclusions:
Elderly persons with low-normal TSH levels have more concurrent depressive symptoms as well as a substantially increased risk of developing a depressive syndrome in the subsequent years. This study identifies low-normal TSH as an important risk factor for depression in the elderly.
Context:
Premature delivery is an important risk factor for child mortality and psychiatric, metabolic, and cardiovascular disease later in life. In the majority of cases, the cause of prematurity ...cannot be identified. Currently, it remains controversial whether abnormal maternal thyroid function during pregnancy increases the risk of premature delivery. Therefore, we investigated the relation between maternal serum thyroid parameters and the risk of premature delivery in a large prospective population-based study.
Design:
Serum TSH, free T4 (FT4), T4, and TPO antibodies (TPOAbs) were determined during early pregnancy in 5971 pregnant women from the Generation R study. Data were available on maternal age, parity, smoking, socioeconomic status, ethnicity, maternal anthropometrics, and urinary iodine levels.
Results:
Of all women, 5.0% had a premature delivery (<37 weeks), 4.4% had a spontaneous premature delivery, and 1.4% had a very premature delivery (<34 weeks). High TSH levels and subclinical hypothyroidism were associated with premature delivery but not with spontaneous premature delivery. Maternal hypothyroxinemia was associated with a 2.5-fold increased risk of premature delivery, a 3.4-fold increased risk of spontaneous premature delivery, and a 3.6-fold increased risk of very premature delivery (all P < .01). TPOAb positivity was associated with a 1.7-fold increased risk of premature delivery (P = .01), a 2.1-fold increased risk of spontaneous premature delivery (P = .02), and a 2.5-fold increased risk of very premature delivery (P = .04). These effects remained similar after correction for TSH and FT4 levels.
Conclusions:
Hypothyroxinemia and TPOAb positivity are associated with an increased risk of premature delivery. The increased risk in TPOAb-positive women seems to be independent of thyroid function.
Every year, mountain pastures show a progressive impoverishment of forage. The loss in grassland feed value restricts the production period of local Pecorino cheeses, which strongly depend on the ...vegetative cycle of the pasture linked to climatic conditions. The Monte Fietone mountain area (Macerata, Italy) has emblematic pasture flora during spring and early summer. This unique environment is normally used for rearing sheep, allowing regular production of local Pecorino cheeses from their milk, which is rich in vitamins and intrinsic floral aromas. Biologists and agronomists are giving increasing importance to these mountain food products. We conducted sensorial tests and experimental auctions to investigate recognition of the quality of this rare artisanal product. The results indicate considerable potential for economic differentiation. Accordingly, we recommend useful and applicable marketing and policy actions to support the sustainability of mountain grazing systems.
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.
Untreated hypothyroidism is associated with acquired von Willebrand syndrome, and hyperthyroidism is associated with increased thrombosis risk. However, the causal effects of thyroid function on ...hemostasis, coagulation, and fibrinolysis are unknown.
In a two-sample Mendelian randomization (MR) study with genome-wide association variants, we assessed causality of genetically predicted hypothyroidism (
= 134,641), normal-range thyrotropin (TSH;
= 54,288) and free thyroxine (fT4) (
= 49,269), hyperthyroidism (
= 51,823), and thyroid peroxidase antibody positivity (
= 25,821) on coagulation (activated partial thromboplastin time, von Willebrand factor VWF, factor VIII FVIII, prothrombin time, factor VII, fibrinogen) and fibrinolysis (D-dimer, tissue plasminogen activator TPA, plasminogen activator inhibitor-1) from the CHARGE Hemostasis Consortium (
= 2583-120,246). Inverse-variance-weighted random effects were the main MR analysis followed by sensitivity analyses. Two-sided
< 0.05 was nominally significant, and
< 0.0011 = 0.05/(5 exposures × 9 outcomes) was Bonferroni significant for the main MR analysis.
Genetically increased TSH was associated with decreased VWF β(SE) = -0.020(0.006),
= 0.001 and with decreased fibrinogen β(SE) = -0.008(0.002),
= 0.001. Genetically increased fT4 was associated with increased VWF β(SE) = 0.028(0.011),
= 0.012. Genetically predicted hyperthyroidism was associated with increased VWF β(SE) = 0.012(0.004),
= 0.006 and increased FVIII β(SE) = 0.013(0.005),
= 0.007. Genetically predicted hypothyroidism and hyperthyroidism were associated with decreased TPA β(SE) = -0.009(0.024),
= 0.024 and increased TPA β(SE) = 0.022(0.008),
= 0.008, respectively. MR sensitivity analyses showed similar direction but lower precision. Other coagulation and fibrinolytic factors were inconclusive.
In the largest genetic studies currently available, genetically increased TSH and fT4 may be associated with decreased and increased synthesis of VWF, respectively. Since Bonferroni correction may be too conservative given the correlation between the analyzed traits, we cannot reject nominal associations of thyroid traits with coagulation or fibrinolytic factors.
Context:
Maternal hyperthyroidism during pregnancy is associated with an increased risk of low birth weight, predisposing to neonatal morbidity and mortality. However, the effects of variation in ...maternal serum thyroid parameters within the normal range on birth weight are largely unknown.
Objective:
The aim was to study the effects of early pregnancy maternal serum thyroid parameters within the normal range on birth weight, as well as the relation between umbilical cord thyroid parameters and birth weight.
Design, Setting, and Participants:
In early pregnancy, serum TSH, FT4 (free T4), and thyroid peroxidase antibody levels were determined in 4464 pregnant women. Cord serum TSH and FT4 levels were determined in 2724 newborns. Small size for gestational age at birth (SGA) was defined as a gestational age-adjusted birth weight below the 2.5th percentile. The associations between normal-range maternal and cord thyroid parameters, birth weight, and SGA were studied using regression analyses.
Results:
In mothers with normal-range FT4 and TSH levels, higher maternal FT4 levels were associated with lower birth weight β = −15.4 (3.6) g/pmol · liter, mean (se); P = 1.6 × 10−5, as well as with an increased risk of SGA newborns odds ratio (95% confidence interval) = 1.09 (1.01–1.17); P = 0.03. Birth weight was positively associated with both cord TSH β = 4.1 (1.4) g/mU · liter; P = 0.007 and FT4 levels β = 23.0 (3.2) g/pmol · liter; P = 9.2 × 10−13.
Conclusions:
We show that maternal high-normal FT4 levels in early pregnancy are associated with lower birth weight and an increased risk of SGA newborns. Additionally, birth weight is positively associated with cord TSH and FT4 levels. These data demonstrate that even mild variation in thyroid function within the normal range can have important fetal consequences.
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