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.
Although the consequences of severe iodine deficiency are beyond doubt, the effects of mild to moderate iodine deficiency in pregnancy on child neurodevelopment are less well established.
To study ...the association between maternal iodine status during pregnancy and child IQ and identify vulnerable time windows of exposure to suboptimal iodine availability.
Meta-analysis of individual participant data from three prospective population-based birth cohorts: Generation R (Netherlands), INMA (Spain), and ALSPAC (United Kingdom); pregnant women were enrolled between 2002 and 2006, 2003 and 2008, and 1990 and 1992, respectively.
General community.
6180 mother-child pairs with measures of urinary iodine and creatinine concentrations in pregnancy and child IQ. Exclusion criteria were multiple pregnancies, fertility treatment, medication affecting the thyroid, and preexisting thyroid disease.
Child nonverbal and verbal IQ assessed at 1.5 to 8 years of age.
There was a positive curvilinear association of urinary iodine/creatinine ratio (UI/Creat) with mean verbal IQ only. UI/Creat <150 µg/g was not associated with lower nonverbal IQ (-0.6 point; 95% CI: -1.7 to 0.4 points; P = 0.246) or lower verbal IQ (-0.6 point; 95% CI: -1.3 to 0.1 points; P = 0.082). Stratified analyses showed that the association of UI/Creat with verbal IQ was only present up to 14 weeks of gestation.
Fetal brain development is vulnerable to mild to moderate iodine deficiency, particularly in the first trimester. Our results show that potential randomized controlled trials investigating the effect of iodine supplementation in women with mild to moderate iodine deficiency on child neurodevelopment should begin supplementation not later than the first trimester.
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.
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.
To study the role of thyroid function in dementia, cognitive function, and subclinical vascular brain disease with MRI.
Analyses were performed within the Rotterdam Study (baseline 1997), a ...prospective, population-based cohort. We evaluated the association of thyroid-stimulating hormone (TSH) and free thyroxine with incident dementia using Cox models adjusted for age, sex, cardiovascular risk factors, and education. Absolute risks were calculated accounting for death as a competing risk factor. Associations of thyroid function with cognitive test scores and subclinical vascular brain disease (white matter lesions, lacunes, and microbleeds) were assessed with linear or logistic regression. Additionally, we stratified by sex and restricted analyses to normal thyroid function.
We included 9,446 participants with a mean age of 65 years. During follow-up (mean 8.0 years), 601 participants had developed dementia. Higher TSH was associated with lower dementia risk in both the full and normal ranges of thyroid function (hazard ratio HR 0.90, 95% confidence interval CI 0.83-0.98; and HR 0.76, 95% CI 0.64-0.91, respectively). This association was independent of cardiovascular risk factors. Dementia risk was higher in individuals with higher free thyroxine (HR 1.04, 95% CI 1.01-1.07). Absolute 10-year dementia risk decreased from 15% to 10% with higher TSH in older women. Higher TSH was associated with better global cognitive scores (p = 0.021). Thyroid function was not related to subclinical vascular brain disease as indicated by MRI.
High and high-normal thyroid function is associated with increased dementia risk. Thyroid function is not related to vascular brain disease as assessed by MRI, suggesting a role for thyroid hormone in nonvascular pathways leading to dementia.
Bisphenols and triclosan are considered as potential thyroid disruptors. While mild alterations in maternal thyroid function can result in adverse pregnancy and child developmental outcomes, there is ...still uncertainty whether bisphenols or triclosan can interfere with thyroid function during pregnancy.
We aimed to investigate the association of urinary bisphenol A (BPA), bisphenol S (BPS), bisphenol F (BPF) and triclosan with early pregnancy thyroid function.
This study was embedded in the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy study (SELMA), a population-based prospective pregnancy cohort. In total, 1996 participants were included in the current study. Maternal urinary concentrations of three bisphenols and triclosan, collected at median (95% range) 10 (6–14) weeks of pregnancy as well as serum concentrations of thyroid stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), total thyroxine (TT4), and total triiodothyronine (TT3) were measured.
Higher BPA levels were associated with lower TT4 concentrations (non-monotonic, P = 0.03), a lower FT4/FT3 ratio (β SE -0.02 0.01, P = 0.03) and a lower TT4/TT3 ratio (β SE -0.73 0.27, P = 0.008). Higher BPF levels were associated with a higher FT3 (β SE 0.01 0.007, P = 0.04). There were no associations between other bisphenols or triclosan and absolute TSH, (F)T4 or (F)T3 concentrations. The association of BPA with thyroid function differed with gestational age. The negative association of BPA with FT4/FT3 and TT4/TT3 ratios was only apparent in early but not late gestation (P for interaction: 0.003, 0.008, respectively).
These human data during pregnancy substantiate experimental findings suggesting that BPA could potentially affect thyroid function and deiodinase activities in early gestation.
•Bisphenol A (BPA) had a non-monotonic association with total T4 in pregnant women.•Higher BPA was associated with lower (F)T4/(F)T3 ratio in very early pregnancy.•Bisphenol F had a positive association with FT3.•Bisphenol S and triclosan were not associated with thyroid function.
•Exposure to phthalates disrupt the maternal thyroid system.•Metabolites of DEHP can disrupt the maternal hypothalamic-pituitary-thyroid axis.•Several phthalates can increase the maternal T4 ...metabolism.•Phthalate substitutes such as DINCH are also capable of thyroid system disruption.
The extent of thyroid disruptive effects of phthalates during pregnancy remains unclear.
To investigate the association of maternal urinary phthalates with markers of the thyroid system during early pregnancy.
Urinary concentrations of phthalate metabolites and serum concentrations of thyroid stimulating hormone (TSH), free and total thyroxine (FT4 and TT4) and free and total triiodothyronine (FT3 and TT3) were measured in pregnant women in early pregnancy in the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy study (2007-ongoing), a population-based prospective cohort.
In the 1,996 included women, higher di-ethyl-hexyl phthalate (DEHP) metabolites were associated with a lower FT4 (β SE for the molar sum: −0.13 0.06, P = 0.03) and a higher TSH/FT4 ratio (0.003 0.001, P = 0.03). Higher concentrations of di-iso-nonyl phthalate (DINP) metabolites were associated with a lower TT4 (β SE for the molar sum: 0.93 0.44, P = 0.03) as well as with lower TT4/FT4 and TT4/TT3 ratios. Higher metabolites of both dibutyl and butyl-benzyl phthalate (DBP and BBzP) were associated with lower T4/T3 ratio (free and total) and higher FT4/TT4 and FT3/TT3 ratios. A higher diisononyl cyclohexane dicarboxylate (DINCH) metabolite concentration was associated with a higher TT3.
These results translate results from experimental studies suggesting that exposure to phthalates may interfere with the thyroid system during pregnancy. This is also true for compounds that have been introduced to replace known disruptive phthalates. Further experimental studies should take into account the human evidence to better investigate the potential underlying mechanisms of thyroid disruption by phthalates.
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.
Abstract
Context
Low maternal free T4 (FT4) has been associated with poor child neurodevelopment in some single-center studies. Evidence remains scarce for the potential adverse effects of high FT4 ...and whether associations differ in countries with different iodine status.
Objective
To assess the association of maternal thyroid function in early pregnancy with child neurodevelopment in countries with a different iodine status.
Design, Setting, and Participants
Meta-analysis of individual participant data from 9036 mother–child pairs from three prospective population-based birth cohorts: INMA Infancia y Medio Ambiente (Environment and Childhood project) (Spain), Generation R (Netherlands), and ALSPAC (Avon Longitudinal Study of Parents and Children, United Kingdom). The exclusion criteria were multiple pregnancies, fertility treatments, thyroid-interfering medication usage, and known thyroid disease.
Main Outcomes
Child nonverbal IQ at 5 to 8 years of age, verbal IQ at 1.5 to 8 years of age, and autistic traits within the clinical range at 5 to 8 years of age.
Results
FT4 <2.5th percentile was associated with a 3.9-point (95% CI, −5.7 to −2.2) lower nonverbal IQ and a 2.1-point (95% CI, −4.0 to −0.1) lower verbal IQ. A suggestive association of hypothyroxinemia with a greater risk of autistic traits was observed. FT4 >97.5th percentile was associated with a 1.9-fold (95% CI, 1.0 to 3.4) greater risk of autistic traits. No independent associations were found with TSH.
Conclusions
Low maternal FT4 was consistently associated with a lower IQ across the cohorts. Further studies are needed to replicate the findings of autistic traits and investigate the potential modifying role of maternal iodine status. FT4 seems a reliable marker of fetal thyroid state in early pregnancy, regardless of the type of immunoassay.
This study confirms that low FT4, but not TSH, during early pregnancy is associated with a lower IQ. We report a suggestive association of hypothyroxinemia and high maternal FT4 with autistic traits.
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.
PDF
