Maternal Hypothyroxinemia Research Articles

The Implications of Iodine and its Supplementation During Pregnancy in Fetal Brain Development

Iodine is an essential trace element for life. Its biological effects are a consequence of its incorporation to the thyroid hormones, which play a crucial role in fetal organogenesis, and in particular in brain development. This takes place during early gestation and involves delicate targeting throughout the central nervous system, including adequate neuronal growth, migration and myelinization at different sites, such as the cerebral cortex and neocortex, visual and auditory cortex, hippocampus and cerebellum. Pregnancy is characterized by an increased demand of thyroid hormones by the feto-placental unit in order to fulfill the necessary requirements of thyroid hormone action for normal fetal development. Up until week 20, the fetal thyroid is not fully active and therefore is completely dependent on the maternal thyroxine supply. Thus, the maternal thyroid has to adapt to this situation by producing about 1.5 fold more thyroxine. This requires that enzymatic gland machinery works normally as well as an adequate iodine intake, the principal substrate for thyroid hormone synthesis. Biological consequences of iodine related maternal hypothyroxinemia are currently very well known, by both experimental models and by clinical and epidemiological evidences. The associated disturbances parallel the degree of maternal thyroxine deficiency, ranging from increased neonatal morbi-mortality and severe mental dysfunction, to hyperactivity, attention disorders and a substantial decrease of IQ of an irreversible nature in the progeny of mothers suffering a deprivation of iodine during pregnancy. As a consequence, iodine deficiency is the leading preventable cause of mental impaired function in the world, affecting as many as 2 billion people (35.2% of the entire population). Prevention of fetal iodine deficiency - a problem of pandemic proportions- is feasible, provided that an iodine supply of 200-300 μg/day to the mother is ensured, before and throughout gestation as well as during the lactating period.

Maternal Hypothyroxinemia in Early Pregnancy Predicts Reduced Performance in Reaction Time Tests in 5- to 6-Year-Old Offspring

Overt hypothyroidism in pregnant women is associated with poorer neurodevelopment in their children. Findings from studies investigating the effect of less severe impairments in the maternal thyroid function on cognitive functioning in offspring are difficult to interpret for a number of reasons, including lack of objective cognitive tests, preschool age at assessment, and small sample sizes. We aimed to assess the effect of the maternal thyroid status in early pregnancy on their offspring's cognitive performance at 5 to 6 years of age. This was a prospective study that included the data of 1765 healthy 5- to 6-year-old children from the Amsterdam Born Children and their Development study. Maternal serum free T4 and TSH were obtained at a median gestational age of 90 (interquartile range, 83 to 100) days. Cognitive performance was tested using a computerized assessment program that measured response speed, response speed stability, visuomotor skills, response selection, and response inhibition. Maternal hypothyroxinemia (ie, maternal free T4 in the lowest 10% of distribution) was associated with a 41.3 (95% confidence interval, 20.3-62.4) ms slower response speed in a simple reaction time task. In this test, it was also associated with a decreased stability in response speed. The relations found persisted after adjustment for family background and perinatal conditions. The effect of hypothyroxinemia on these outcomes was dependent on its interaction with TSH level. Lower maternal free T4 concentration at the end of the first trimester predicted slower response speed and decreased stability in response speed in offspring at 5 to 6 years of age.

Maternal hypothyroxinaemia in early pregnancy is associated with reduced performance in reaction time tests in 5-to-6-yearold offspring

s ingediend voor het Amsterdam Kindersymposium 2013 41 Maternal hypothyroxinaemia in early pregnancy is associated with reduced performance in reaction time tests in 5-to-6-yearold offspring Martijn J.J. Finken (1), Manon van Eijsden (2), Eva M. Loomans (2), Tanja G.M. Vrijkotte (3), Joost Rotteveel (1) (1) VUmc (2) GGD Amsterdam (3) AMC INTRODUCTION Overt hypothyroidism in pregnant women is associated with poorer neurodevelopment in their children. Findings from studies investigating the eff ect of less severe impairments in the maternal thyroid function on cognitive functioning in off spring are diffi cult to interpret for a number of reasons, including lack of objective cognitive tests, pre-school age at assessment, and small sample sizes. We tested whether normal variation in the maternal thyroid function was associated with scores on cognitive tests that assess basic attention and information-processing functions in off spring at school age. METHODS This study was part of the Amsterdam Born Children and their Development (ABCD) study, which follows a population-based cohort of mothers and children. Maternal serum free thyroxin (T4) and thyrotropin (TSH) were obtained at the end of the fi rst trimester. In off spring at the age of 5-6 years, cognitive functioning was tested, using a computerized assessment program. Data were complete for 1,765 mother-child pairs. RESULTS Maternal hypothyroxinaemia (ie, maternal free T4 in the lowest 10% of distribution) was associated with a 42.4 (95% confi dence interval: 21.4-63.4) ms slower response speed in the simple reaction time task. It was also associated with a decreased stability in response speed. The relations found persisted after adjustment for the family background and perinatal conditions. None of the outcomes was robustly related to the maternal TSH level. CONCLUSION Lower maternal free T4 concentrations at the end of the fi rst trimester predicted slower response speed and decreased stability in response speed in off spring at 5-6 years of age.

Obstetric controversies in thyroidology

It is well known that thyroid disorders commonly affect women. The care of pregnant women affected by thyroid disease is an important clinical challenge for endocrinologists. Hypothyroidism is the commonest problem, and maternal hypothyroxinemia has been linked to adverse feto-maternal outcomes. This article would discuss the controversy regarding first-trimester thyroid hormone deficiency and fetal brain development. Certain obstetric controversies in the management of hyperthyroidism in pregnancy, including the indications of TSH receptor antibody measurements and fetal thyroid status monitoring would also be discussed.

Maternal Hypothyroxinemia During Pregnancy and Growth of the Fetal and Infant Head

Severe maternal thyroid dysfunction during pregnancy affects fetal brain growth and corticogenesis. This study focused on the effect of maternal hypothyroxinemia during early pregnancy on growth of the fetal and infant head. In a population-based birth cohort, we assessed thyroid status in early pregnancy (median 13.4, 90% range 10.8-17.2), in 4894 women, and measured the prenatal and postnatal head size of their children at 5 time points. Hypothyroxinemia was defined as normal thyroid-stimulating hormone levels and free thyroxine-4 concentrations below the 10th percentile. Statistical analysis was performed using linear generalized estimating equation. Maternal hypothyroxinemia was associated with larger fetal and infant head size (overall estimate β: 1.38, 95% confidence interval 0.56; 2.19, P = .001). In conclusion, in the general population, even small variations in maternal thyroid function during pregnancy may affect the developing head of the young child.

Hypothyroxinemia during pregnancy: the effect on neurodevelopment in the child

ContextExperimental studies have shown that maternal hypothyroxinemia during early pregnancy is associated with poor neurodevelopment in affected offspring. ObjectiveThe aim of this study was to assess the impact of maternal serum free T4 on psychomotor development of offspring. Materials and methodsThe study involved 147 women in the third trimester (week 37) of pregnancy. TSH and free T4 serum levels were measured at 37 week gestation. The children were evaluated between 38 and 60 months of age by the McCarthy Scales of Children's Abilities. Results54.4% of the women had a free T4 below the threshold of hypothyroxinemia. We find a significant effect of maternal hypothyroxinemia on the general cognitive index, and on perceptual-manipulative and memory coefficients.

Developmental triclosan exposure decreases maternal, fetal, and early neonatal thyroxine: A dynamic and kinetic evaluation of a putative mode-of-action

This work tests the mode-of-action (MOA) hypothesis that maternal and developmental triclosan (TCS) exposure decreases circulating thyroxine (T4) concentrations via up-regulation of hepatic catabolism and elimination of T4. Time-pregnant Long-Evans rats received TCS po (0–300mg/kg/day) from gestational day (GD) 6 through postnatal day (PND) 21. Serum and liver were collected from dams (GD20, PND22) and offspring (GD20, PND4, PND14, PND21). Serum T4, triiodothyronine (T3), and thyroid-stimulating hormone (TSH) concentrations were measured by radioimmunoassay. Ethoxy-O-deethylase (EROD), pentoxyresorufin-O-depentylase (PROD) and uridine diphosphate glucuronyltransferase (UGT) enzyme activities were measured in liver microsomes. Custom Taqman® qPCR arrays were employed to measure hepatic mRNA expression of select cytochrome P450s, UGTs, sulfotransferases, transporters, and thyroid hormone-responsive genes. TCS was quantified by LC/MS/MS in serum and liver. Serum T4 decreased approximately 30% in GD20 dams and fetuses, PND4 pups and PND22 dams (300mg/kg/day). Hepatic PROD activity increased 2–3 fold in PND4 pups and PND22 dams, and UGT activity was 1.5 fold higher in PND22 dams only (300mg/kg/day). Minor up-regulation of Cyp2b and Cyp3a expression in dams was consistent with hypothesized activation of the constitutive androstane and/or pregnane X receptor. T4 reductions of 30% for dams and GD20 and PND4 offspring with concomitant increases in PROD (PND4 neonates and PND22 dams) and UGT activity (PND22 dams) suggest that up-regulated hepatic catabolism may contribute to TCS-induced hypothyroxinemia during development. Serum and liver TCS concentrations demonstrated greater fetal than postnatal internal exposure, consistent with the lack of T4 changes in PND14 and PND21 offspring. These data support the MOA hypothesis that TCS exposure leads to hypothyroxinemia via increased hepatic catabolism; however, the minor effects on thyroid hormone metabolism may reflect the low efficacy of TCS as thyroid hormone disruptor or highlight the possibility that other MOAs may also contribute to the observed maternal and early neonatal hypothyroxinemia.

Prenatal iodine deficiency results in structurally and functionally immature lungs in neonatal rats

Maternal hypothyroidism affects postnatal lung structure. High prevalence of hypothyroxinemia (low T4, normal T3) in iodine-deficient pregnant women and associated risk for neuropsychological development along with high infant/neonatal mortality ascribed to respiratory distress prompted us to study the effects of maternal hypothyroxinemia on postnatal lung development. Female Sprague Dawley rats were given a low-iodine diet (LID) with 1% KClO(4) in drinking water for 10 days, to minimize thyroid hormone differences. Half of these rats were continued on iodine-deficient diet; ID (LID with 0.005% KClO(4)) for 3 mo, whereas the rest were switched to an iodine-sufficient diet; IS [LID + potassium iodide (10 μg iodine/20 g of diet + normal drinking water)]. Pups born to ID mothers were compared with age-matched pups from IS mothers at postnatal days 8 (P8) and 16 (P16) (n = 6-8/group). ID pups had normal circulating T3 but significantly low T4 levels (P < 0.05) and concomitantly approximately sixfold higher thyroid hormone receptor-β mRNA in alveolar epithelium. Lung histology revealed larger and irregularly shaped alveoli in ID pups relative to controls. Lung function was assessed at P16 using a double-chambered plethysmograph and observed reduced tidal volume, peak inspiratory and expiratory flow, and dynamic lung compliance in ID pups compared with IS pups. Significant lowering of surfactant protein (SP)-B and SP-C mRNA and protein found in ID pups at P16. ID pups had 16-fold lower matrix metalloproteinase-9 mRNA levels in their alveolar epithelium. In addition, mRNA levels of thyroid transcription factor-1 and SP-D were significantly higher (3-fold) compared with IS pups. At P16, significantly lower levels of SP-B and SP-C found in ID pups may be responsible for immature lung development and reduced lung compliance. Our data suggest that maternal hypothyroxinemia may result in the development of immature lungs that, through respiratory distress, could contribute to the observed high infant mortality in ID neonates.

Correlation between hypothyroidism and thyroid peroxidase antibody during the second trimester

Objective To investigate the prevalence of hypothyroidism during the second trimester and its relationship with thyroid peroxidase antibody (TPOAb). Methods Two thousand one hundred and forty one pregnant women whose gestational age between 14 to 28 weeks,accepted their prenatal care at the outpatient clinic of International Peace Maternity & Child Health Hospital from March 1,2010 to July 31,2010 were enrolled into this study. Serum TPOAb,thyroidstimulating hormone (TSH) and free thyroxine (FT4) of these women were detected. Logistic regression model was used to analyze the risk factors of subclinical hypothyroidism and positive TPOAb,while Spearman rank correlation was used to analyze the relationship between the levels of TSH,FT4 and TPOAb. Results (1) Subclinical hypothyroidism was detected in 13.36％ (286/2141) patients. Isolated maternal hypothyroxinemia occurs in 0.14％ (3/2141) of pregnant women.No overt hypothyroidism patient was detected and 6.26％ (134/2141) of all pregnant women exhibited positive TPOAb(≥50 U/ml).(2) Positive rate of TPOAb in subclinical hypothyroidism group,isolated maternal hypothyroxinemia group and normal thyroid function group was 13.64％ (39/286),0/3 and 5.06％ (86/1701) respectively,and there was difference among the three groups (x2 =30.82,P＜0.01).The positive rate of TPOAb did not relate to fetal gender,maternal age,gestational age,gravidity and parity.(3) TPOAb had positive relationship with TSH level (r=0.12,P＜0.01),while did not relate to FT4 level (r=-0.04,P=0.09). (4) Positive TPOAb (OR 3.18,95％ CI:2.10-4.83,P＜0.01) and gravidity (OR=1.21,95％ CI:1.02-1.43,P=0.030)were risk factors of subclinical hypothyroidism. Conclusions Hypothyroidism is common during the second trimester. It is necessary to screen TPOAb in pregnant women as TPOAb is an independent and important predictor of subclinical hypothyroidism. Key words: Pregnancy complications; Hypothyroidism; Iodide peroxidase; Autoantibodies

The expression of thyroid hormone transporters in the human fetal cerebral cortex during early development and in N-Tera-2 neurodifferentiation.

Associations of neurological impairment with mutations in the thyroid hormone (TH) transporter, MCT8, and with maternal hypothyroxinaemia, suggest that THs are crucial for human fetal brain development. It has been postulated that TH transporters regulate the cellular supply of THs within the fetal brain during development. This study describes the expression of TH transporters in the human fetal cerebral cortex (7–20 weeks gestation) and during retinoic acid induced neurodifferentiation of the human N-Tera-2 (NT2) cell line, in triiodothyronine (T3) replete and T3-depleted media. Compared with adult cortex, mRNAs encoding OATP1A2, OATP1C1, OATP3A1 variant 2, OATP4A1, LAT2 and CD98 were reduced in fetal cortex at different gestational ages, whilst mRNAs encoding MCT8, MCT10, OATP3A1 variant 1 and LAT1 were similar. From the early first trimester, immunohistochemistry localised MCT8 and MCT10 to the microvasculature and to undifferentiated CNS cells. With neurodifferentiation, NT2 cells demonstrated declining T3 uptake, accompanied by reduced expressions of MCT8, LAT1, CD98 and OATP4A1. T3 depletion significantly reduced MCT10 and LAT2 mRNA expression at specific time points during neurodifferentiation but there were no effects upon T3 uptake, neurodifferentiation marker expression or neurite lengths and branching. MCT8 repression also did not affect NT2 neurodifferentiation. In conclusion, many TH transporters are expressed in the human fetal cerebral cortex from the first trimester, which could regulate cellular TH supply during early development. However, human NT2 neurodifferentiation is not dependent upon T3 or MCT8 and there were no compensatory changes to promote T3 uptake in a T3-depleted environment.

Bayesian adjustment for measurement error in continuous exposures in an individually matched case-control study.

BackgroundIn epidemiological studies explanatory variables are frequently subject to measurement error. The aim of this paper is to develop a Bayesian method to correct for measurement error in multiple continuous exposures in individually matched case-control studies. This is a topic that has not been widely investigated. The new method is illustrated using data from an individually matched case-control study of the association between thyroid hormone levels during pregnancy and exposure to perfluorinated acids. The objective of the motivating study was to examine the risk of maternal hypothyroxinemia due to exposure to three perfluorinated acids measured on a continuous scale. Results from the proposed method are compared with those obtained from a naive analysis.MethodsUsing a Bayesian approach, the developed method considers a classical measurement error model for the exposures, as well as the conditional logistic regression likelihood as the disease model, together with a random-effect exposure model. Proper and diffuse prior distributions are assigned, and results from a quality control experiment are used to estimate the perfluorinated acids' measurement error variability. As a result, posterior distributions and 95% credible intervals of the odds ratios are computed. A sensitivity analysis of method's performance in this particular application with different measurement error variability was performed.ResultsThe proposed Bayesian method to correct for measurement error is feasible and can be implemented using statistical software. For the study on perfluorinated acids, a comparison of the inferences which are corrected for measurement error to those which ignore it indicates that little adjustment is manifested for the level of measurement error actually exhibited in the exposures. Nevertheless, a sensitivity analysis shows that more substantial adjustments arise if larger measurement errors are assumed.ConclusionsIn individually matched case-control studies, the use of conditional logistic regression likelihood as a disease model in the presence of measurement error in multiple continuous exposures can be justified by having a random-effect exposure model. The proposed method can be successfully implemented in WinBUGS to correct individually matched case-control studies for several mismeasured continuous exposures under a classical measurement error model.

Current questions of thyroid diseases in childhood

In recent years our knowledge on thyroid diseases in childhood has been increased. Several forms of congenital hypothyroidism (dysgenesis, dyshormongenesis, thyrotropin resistance and some central forms) are consequences of gene mutations. Maternal hypothyroxinemia due to severe iodine deficiency leads to early neurological damage and congenital hypothyroidism. Neonatal screening of congenital hypothyroidism and early treatment with l-thyroxin ensure good prognosis. Differential diagnosis of the various forms of congenital hypothyroidism in newborns is not an easy task. The need for treatment of transient hypothyroxinemia is still controversial. Diagnosis of juvenile lymphocytic thyroiditis can be ascertained by the clinical status, ultrasound examination, detection of anti-peroxydase antibodies, evaluation of thyroid function, and fine needle aspiration cytology. L-thyroxin therapy is recommended in cases of subclinical and manifest hypothyroidism. The transient form of the rare newborn hyperthyroidism is the consequence of maternal Graves-Basedow disease. It can be a sever condition and its permanent form is caused by TSH-receptor gene mutation. In the pathogenesis of autonomic thyroid adenoma mutations of the TSH-receptor and the alpha subunit of the stimulatory G-protein are involved. Treatment of Graves-Basedow disease in childhood is a debated question. The first choice is medical treatment with antithyroid and beta-blocking drugs. However, remission rate is low under this therapy, and the disease is characterised by frequent relapses. For this reason, the necessity of definitive therapy frequently arises. In Europe subtotal thyroidectomy is used as second choice of therapy, but clinical experience in the United States showed that radioiodine treatment is a safe and effective therapy for children and adolescents. Iodine deficient goitre in childhood is a form of iodine deficiency disorder. It is the consequence of adaptation to iodine deficiency. It can be treated by iodine or/and l-thyroxin, and its development can be prevented by iodinated salt. In childhood, thyroid nodule needs for a detailed investigation because of the possibility of thyroid cancer. Medullar thyroid carcinoma indicates genetic screening in the patients and their family, and the presence of disease-causing RET-proto-oncogene mutation confirms the need for total thyroidectomy already in childhood.

Perfluorinated acids and hypothyroxinemia in pregnant women

Perfluorinated acids (PFAs) are prominent and widespread contaminants of human blood. In animal studies there is evidence that suggests certain PFAs can disrupt thyroid hormone homeostasis. A commonly reported condition in exposed animals is hypothyroxinemia, whereby serum free thyroxine (fT4) is decreased despite normal thyroid stimulating hormone (TSH) concentrations. We designed an individually matched case-control study to investigate whether exposure to perfluorooctanoate (PFOA), perfluorohexane sulfonate (PFHxS), and perfluorooctane sulfonate (PFOS) was associated with hypothyroxinemia in pregnant women from Edmonton, Alberta, Canada, in 2005–2006, who underwent a “triple screen” blood test at 15–20 weeks gestation as part of ante-natal care. Thyroid hormones, fT4 and TSH, were measured in serum from 974 women, and from these we measured PFAs in the sera of 96 hypothyroxinemic cases (normal TSH, the lowest 10th percentile of fT4) and 175 controls (normal TSH, fT4 between the 50th and 90th percentiles) matched on age and referring physician. Analyses by conditional logistic regression indicated that the concentrations of PFAs in this population were not associated with hypothyroxinemia among pregnant women. The current findings do not support a causal link between PFA exposure and maternal hypothyroxinemia in the studied population.

Exposure to the Widely Used Fungicide Mancozeb Causes Thyroid Hormone Disruption in Rat Dams but No Behavioral Effects in the Offspring

The widely used fungicide mancozeb has been shown to cause hypothyroxinemia and other adverse effects on the thyroid hormone system in adult experimental animals. In humans, hypothyroxinemia early in pregnancy is associated with adverse effects on the developing nervous system and can lead to impaired cognitive function and motor development in children. The aim of the present study was therefore to assess whether perinatal mancozeb exposure would cause developmental neurotoxicity in rats. Groups of 9-21 time-mated Wistar rats were dosed with 0, 50, 100, or 150 mg mancozeb/kg body weight (bw)/day by gavage from gestation day (GD) 7 to postnatal day (PND) 16, and total thyroxine (T(4)) levels were measured in dams during gestation. On PND 16, hormone levels and several organ weights were measured in the offspring, whereas motor activity, startle response, and cognitive function were assessed in the adult offspring. The dose of 150 mg/kg/day caused neurotoxicity in the pregnant dams and was therefore reduced to 100 mg/kg bw/day in mid study. T(4) levels showed a dose-dependent and significant decrease in dams from all three dose groups on GD 15, whereas offspring T(4) levels, thyroid weights, and histology were unaffected on PND 16. No effects on reproductive organ weights were seen, and no behavioral changes were observed. Taken together, these results indicate that in rats, moderate maternal hypothyroxinemia during gestation does not necessarily lead to hyperactivity or reduced special learning abilities in the offspring. Mancozeb exposure did, however, reduce T(4) levels in dams and may therefore still be a potential contributor to thyroid disruption in humans and in result adversely affects the developing brain.

Thyroid hormones and fetal neurological development

The development of fetal thyroid function is dependent on the embryogenesis, differentiation, and maturation of the thyroid gland. This is coupled with evolution of the hypothalamic-pituitary-thyroid axis and thyroid hormone metabolism, resulting in the regulation of thyroid hormone action, production, and secretion. Throughout gestation there is a steady supply of maternal thyroxine (T(4)) which has been observed in embryonic circulation as early as 4 weeks post-implantation. This is essential for normal early fetal neurogenesis. Triiodothyronine concentrations remain very low during gestation due to metabolism via placental and fetal deiodinase type 3. T(4) concentrations are highly regulated to maintain low concentrations, essential for protecting the fetus and reaching key neurological sites such as the cerebral cortex at specific developmental stages. There are many known cell membrane thyroid hormone transporters in fetal brain that play an essential role in regulating thyroid hormone concentrations in key structures. They also provide the route for intracellular thyroid hormone interaction with associated thyroid hormone receptors, which activate their action. There is a growing body of experimental evidence from rats and humans to suggest that even mild maternal hypothyroxinemia may lead to abnormalities in fetal neurological development. Our review will focus on the ontogeny of thyroid hormone in fetal development, with a focus on cell membrane transporters and TR action in the brain.

Doubts and Concerns about Isolated Maternal Hypothyroxinemia

There is evidence that isolated maternal hypothyroxinemia may have detrimental effects on both mother and foetus. Nonetheless, this condition is still far from being universally accepted as a separate thyroid disease, and a standard definition of this state of mild thyroid underfunction is still lacking. We will review the biochemical criteria used to define isolated maternal hypothyroxinemia, together with current methodological issues related to FT4 assays. We will also discuss its epidemiological impact in both iodine-deficient and-sufficient areas, and the effectiveness of iodine prophylaxis on maternal thyroid function and neuropsychomotor development in offspring.

Thyroid and pregnancy.

Thyroid and pregnancy.

Effect of hypothyroxinemia on thyroid hormone responsiveness and action during rat postnatal neocortical development

Neurological deficits due to maternal and neonatal hypothyroxinemia under mild–moderate iodine deficiency are a major preventable health problem worldwide. The present study assesses the impact of hypothyroxinemia on postnatal neocortical development and also compares it to the known effects of severe hypothyroidism. Our results strongly suggest that even within elevated circulating triiodothyronine (T3) levels, hypothyroxinemia significantly impairs thyroid hormone responsiveness in developing rat neocortex. The significant compensatory alteration in deiodinase levels with unaltered monocarboxylate transporter 8 (MCT8) and thyroid hormone receptors (TRs), although found to be similar in hypothyroxinemic and hypothyroid condition, is more pronounced under later condition. The resultant downregulation of nuclear myelin binding protein (MBP) and mitochondrial transcripts Cytochrome oxidase III (Cox III) as well as significantly enhanced mitochondrial localization of Bax and reduced Bcl-2 and Bcl-xL accompanied by enhanced release of Cytochrome c and Smac with activation of caspase-3 indicates pronounced apoptosis leading to compromised cellular survival. The similarities of this responsiveness albeit with difference in degree under hypothyroidism and hypothyroxinemic state with adequate availability of T3 are suggestive of an independent role of thyroxine in neocortex development. Taken together, this study brings forth the neurophysiological aspects of hypothyroxinemia and underscores the importance of adequate iodine nutrition along with mandatory thyroxin monitoring during pregnancy and after birth.

Subclinical hypothyroidism and related biochemical entities in pregnancy: implications and management.

Subclinical hypothyroidism (SCH), thyroid autoimmunity and isolated maternal hypothyroxinaemia are diagnoses made on laboratory findings. The two former conditions are commonly identified in the general population, while the term isolated maternal hypothyroxinaemia was developed to highlight potential neurodevelopmental risks in progeny. Each entity has been associated with either obstetric, perinatal and/or child developmental harm in observational studies, although few interventional trials have been performed to guide diagnostic and therapeutic approaches. Once diagnosed, treatment of SCH is recommended by endocrine groups to limit potential risk, given that harm from appropriate therapy is unlikely. Screening for thyroid disorders in pregnancy has traditionally been controversial. Definitive trials are expected to report over coming years and updated consensus guidelines will hopefully resolve this issue.

Pregnancy in women heterozygous for MCT8 mutations: risk of maternal hypothyroxinemia and fetal care

Monocarboxylate transporter 8 (MCT8 or SLC16A2) mutations cause X-linked Allan-Herndon-Dudley syndrome. Heterozygous females are usually asymptomatic, but pregnancy may modify thyroid function and MCT8 is expressed in the placenta, suggesting that maternal and fetal abnormalities might develop even in the absence of MCT8 fetal mutation. Genetic counseling is so far based on X-linked transmission, and prenatal diagnosis is rarely performed. To describe thyroid function and the prenatal diagnosis in pregnant mothers harboring heterozygous MCT8 mutations and management of the persistent maternal hypothyroxinemia. Patients Two women heterozygous for MCT8 mutations (c.1690G>A and c.1393-1G>C) were monitored throughout pregnancy. Prenatal diagnosis included sex determination, direct MCT8 sequencing, and familial linkage analysis. Ultrasonography and hormonal assays for maternal thyroid function evaluation were performed serially during pregnancy. Neonatal thyroid hormonal status was assessed. None of the three fetuses (two males and one female) carried MCT8 mutations. One of the two heterozygous mothers revealed gestational hypothyroxinemia, prompting early levothyroxine (l-T₄) therapy until delivery. The second heterozygous mother showed normal thyroid function but was preventively traited by l-T₄ and all of the three neonates had normal thyroid hormone levels and thyroid gland at birth, suggesting advantages of prenatal care and/or compensatory mechanisms. Heterozygous MCT8 women should be monitored for requirement of l-T₄ therapy to prevent fetal and neonatal hypothyroidism and to avoid risk of potential cognitive delay due to gestational hypothyroxinemia. Moreover, when the disease-causing mutation is known and/or the first child is affected, prenatal diagnosis for male fetuses should be assessed early for MCT8 mutations by direct sequencing.