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Background: In the last 2 decades, several studies have examined the association between maternal thyroid hormone insufficiency during pregnancy and neurodevelopmental disorders in children and shown conflicting results., Aim: This systematic review aimed to assess the evidence for an association between maternal thyroid hormone insufficiency during pregnancy and neurodevelopmental disorders in children. We also sought to assess whether levothyroxine treatment for maternal thyroid hormone insufficiency improves child neurodevelopment outcomes., Methods: We performed systematic literature searches in MEDLINE, EMBASE, PSYCinfo, CINAHL, AMED, BNI, Cochrane, Scopus, Web of Science, GreyLit, Grey Source and Open Grey (latest search: March 2017). We also conducted targeted web searching and performed forwards and backwards citation chasing. Meta-analyses of eligible studies were carried out using the random-effects model., Results: We identified 39 eligible articles (37 observational studies and 2 randomized controlled trials [RCT]). Meta-analysis showed that maternal subclinical hypothyroidism and hypothyroxinaemia are associated with indicators of intellectual disability in offspring (odds ratio [OR] 2.14, 95% confidence interval [CI] 1.20 to 3.83, P = .01, and OR 1.63, 95% CI 1.03 to 2.56, P = .04, respectively). Maternal subclinical hypothyroidism and hypothyroxinaemia were not associated with attention deficit hyperactivity disorder, and their effect on the risk of autism in offspring was unclear. Meta-analysis of RCTs showed no evidence that levothyroxine treatment for maternal hypothyroxinaemia or subclinical hypothyroidism reduces the incidence of low intelligence quotient in offspring., Limitations: Although studies were generally of good quality, there was evidence of heterogeneity between the included observational studies (I 2 72%-79%)., Conclusion: Maternal hypothyroxinaemia and subclinical hypothyroidism may be associated with intellectual disability in offspring. Currently, there is no evidence that levothyroxine treatment, when initiated 8- to 20-week gestation (mostly between 12 and 17 weeks), for mild maternal thyroid hormone insufficiency during pregnancy reduces intellectual disability in offspring., (© 2018 The Authors. Clinical Endocrinology Published by John Wiley & Sons Ltd.)

Thyroid hormones (TH) play crucial roles in brain maturation and are important for neuronal migration and neocortical lamination. Subcortical band heterotopia (SBH) represent a class of neuronal migration errors in humans that are often associated with childhood epilepsy. We have previously reported the presence of SBH in a rodent model of low level hypothyroidism induced by maternal exposure to the goitrogen, propylthiouracil (PTU). In the present study, we report the dose-response characteristics of this developmental malformation and the connectivity of heterotopic neurones with other brain regions, as well as their functionality. Pregnant rats were exposed to varying concentrations of PTU through the drinking water (0-10 p.p.m.) beginning on gestational day 6 to produce graded levels of TH insufficiency. Dose-dependent increases in the volume of the SBH present in the corpus callosum were documented in the adult offspring, with a clear presence at concentrations of PTU that resulted in minor (< 15%) reductions in maternal serum thyroxine as measured when pups were weaned. SBH contain neurones, oligodendrocytes, astrocytes and microglia. Monoaminergic and cholinergic processes were prevalent and many of the axons were myelinated. Anatomical connectivity of SBH neurones to cortical neurones and the synaptic functionality of these anatomical connections was verified by ex vivo field potential recordings. SBH persisted in adult offspring despite a return to euthyroid status on termination of exposure and these offspring displayed an increased sensitivity to seizures. Features of this model are attractive with respect to the investigation of the molecular mechanisms of cortical development, the effectiveness of therapeutic intervention in hypothyroxinaemia during pregnancy and the impact of the very modest TH imbalance that accompanies exposure to environmental contaminants., (© Published 2014. This article is a U.S. Government work and is in the public domain in the USA.)

Aims: Iodine is essential for the synthesis of thyroid hormone. Iodine deficiency (ID)-induced hypothyroxinaemia and hypothyroidism during developmental period contribute to impairments of function in the brain, such as psychomotor and motor alterations. However, the mechanisms are still unclear. Therefore, the present research is to study the effects of developmental hypothyroxinaemia caused by mild ID and developmental hypothyroidism caused by severe ID or methimazole (MMZ) on dendritic growth in filial cerebellar Purkinje cells (PCs) and the underlying mechanisms., Methods: A maternal hypothyroxinaemia model was established in Wistar rats using a mild ID diet, and two maternal hypothyroidism models were developed with either severe ID diet or MMZ water. We examined the total dendritic length using immunofluorescence, and Western blot analysis was conducted to investigate the activity of microtubule-associated protein 2 (MAP2), stathmin and calcium/calmodulin-dependent protein kinase II (CaMKII)., Results: Hypothyroxinaemia and hypothyroidism reduced the total dendritic length of cerebellar PCs, decreased MAP2 and its phosphorylation, increased stathmin but reduced its phosphorylation and down-regulated the activity of CaMKII and its phosphorylation in cerebellar PCs on postnatal day (PN) 7, PN14 and PN21., Conclusion: Developmental hypothyroxinaemia induced by mild ID and hypothyroidism induced by severe ID or MMZ limit PCs dendritic growth, which may involve in the disturbance of MAP2 and stathmin in a CaMKII-dependent manner. It suggests a potential mechanism of motor coordination impairments caused by developmental hypothyroxinaemia and hypothyroidism., (© 2013 British Neuropathological Society.)

Hypothyroxinaemia early in pregnancy may impair fetal brain development. Increased body weight has been associated with low thyroxine concentrations in non-pregnant women. In pregnant women, morbid maternal obesity is a risk factor for thyroid dysfunction. But whether lesser degrees of overweight that are much more common could be a risk factor for hypothyroxinaemia in pregnancy is unclear. The objective of this study was to investigate if overweight increases risk for thyroid dysfunction, and specifically hypothyroxinaemia, in iodine-deficient pregnant women. We performed a cross-sectional study at first hospital visit among healthy Thai pregnant women. We measured weight and height, urinary iodine concentration (UIC), serum thyroid hormones and thyroglobulin. Pre-pregnancy weight and relevant dietary factors were determined by questionnaire, and body mass index (BMI) was used to classify weight status. Among 514 women (mean gestational age, 11 weeks) with a median UIC of 111 μg dL(-1) , indicating mild iodine deficiency, 12% had low free thyroxine (fT4) concentrations: 3% had overt hypothyroidism; 7% had subclinical hypothyroidism; and 8% had isolated hypothyroxinaemia. Based on pre-pregnancy BMI, 26% of women were overweight or obese. In a multiple regression model, BMI was a negative predictor of fT4 (β = -0.20, P < 0.001). Compared to normal weight women, the prevalence ratio (95% CI) of a low fT4 in overweight women was 3.64 (2.08-6.37) (P < 0.01). Iodine-deficient pregnant Thai women who are overweight have a 3.6-fold higher risk of hypothyroxinaemia in the first trimester compared to normal weight women. Targeted screening should consider overweight a potential risk factor for thyroid dysfunction in pregnant women in iodine-deficient areas., (© 2013 John Wiley & Sons Ltd.)

Iodine is essential for the biosynthesis of thyroid hormones, including triiodothyronine and thyroxine. Thyroid hormones are important for central nervous system development. Mild maternal iodine deficiency (ID)-induced hypothyroxinaemia causes neurological deficits and mental retardation of the foetus. However, the detailed mechanism underlying these deficits is still largely unknown. Given that the growth-associated protein of 43 kDa (GAP-43), semaphorin 3A (Sema3A) and the glycogen synthase kinase 3β (GSK3β)/collapsin response mediator protein 2 (CRMP2) pathway are essential for axonal development, we hypothesise that hippocampal axonal growth-related proteins may be impaired, which may contribute to hippocampal axonal growth delay in rat offspring exposed to maternal hypothyroxinaemia. To test this hypothesis, maternal hypothyroxinaemia models were established in Wistar rats using a mild ID diet. Besides a negative control group, two maternal hypothyroidism models were created with either a severe ID diet or methimazole in the water. Our results showed that maternal hypothyroxinaemia exposure delayed offspring axonal growth on gestational day 19, postnatal day (PN) 7, PN14 and PN21. Consistent with this, the mean intensity of hippocampal CRMP2 and Tau1 immunofluorescence axonal protein was reduced in the mild ID group. Moreover, maternal hypothyroxinaemia disrupted expressions of GAP-43 and Sema3A. Furthermore, the phosphorylation of GSK3β and CRMP2 was also affected in the treated offspring, implying a potential mechanism by which hypothyroxinaemia-exposure affects neurodevelopment. Taken together, our data support the hypothesis that maternal hypothyroxinaemia may impair axonal growth of the offspring., (© 2013 British Society for Neuroendocrinology.)

Objective: To investigate the relationship between specific thyroid abnormalities in women during pregnancy and the subsequent neuropsychological development of their offspring. Methods: A systematic literature search of PubMed, Embase and Web of Science was conducted. Eligible studies were case-control or cohort study that explored this association with euthyroid thyroid abnormalities during pregnancy. The outcomes included intelligence scores and motor scores. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated and heterogeneity was assessed with Cochrane Q chi-square test and I2 statistics. A fixed-effects or random-effects model was used to pool the estimates according to the heterogeneity among the included studies. Results: Six studies, involving 4449 participants, were included. Children of women with thyroid abnormalities had mean intelligence score of 6.27 points and motor score of 5.99 points lower than that of children of euthyroid women. Subgroup analysis suggested that, children of women with hypothyroxinaemia, subclinical hypothyroidism and positive TPOAb had mean intelligence scores of 5.69 points, 8.76 points and 10.55 points, and mean motor scores of 4.19 points, 9.98 points and 9.03 points lower than those of the controls, respectively. Conclusions: The thyroid abnormalities in pregnant women may adversely affect neuropsychological development of their offspring. [ABSTRACT FROM AUTHOR]

Unlabelled: Transient hypothyroxinaemia with normal thyroid stimulating hormone (TSH) levels is a well-known condition in preterm neonates and is generally assumed to be a harmless epiphenomenon of prematurity. This assumption is, however, based on studies that included very few neonates with a gestational age (GA) below 30 weeks. We therefore measured serum free thyroxine (FT4) and serum TSH on days 1 and 14 in 263 neonates with a GA between 26 and 41 weeks. In 13 infants (5%), transient hypothyroidism (low FT4 and TSH >20 mU/l on day 14) was found. In the remaining 250 patients FT4 on days 1 and 14 but not TSH correlated positively with GA. In neonates with a GA of 35-41 weeks, FT4 increased postnatally to levels within or above the normal adult range. In contrast, in the very preterm group (26-31 weeks) the already low FT4 levels declined to values significantly below the range observed in term neonates. A significant proportion of these neonates had FT4 levels within the hypothyroid range. There was no difference in thyroid function between neonates treated with povidone-iodine or chlorhexidine.Conclusion: Very preterm neonates have FT4 levels on day 14 that are much lower than is generally assumed while TSH remains in the normal range. We therefore propose to measure FT4 in all preterms with a GA below 33 weeks, during the 2nd week of life. [ABSTRACT FROM AUTHOR]