Maternal Hyperthyroidism Research Articles

Navigating thyroid disorders in pregnancy: Minutes of the special symposium of ESICON 2023

Thyroid disorders are among the most common endocrine conditions that can affect pregnancy. Maternal thyroid dysfunction, including both hypothyroidism and hyperthyroidism, can significantly impact pregnancy outcomes and fetal development. Thyroid hormone regulation is crucial for normal fetal brain development, particularly during the first trimester when the fetus is entirely dependent on maternal thyroid hormones. This review aims to provide an overview of the physiological changes in thyroid function during pregnancy, discuss common thyroid disorders, their diagnosis, and management strategies, and highlight the importance of early detection and appropriate treatment to optimize maternal and fetal outcomes. A comprehensive literature search was conducted using major medical databases for articles related to thyroid disorders in pregnancy, including hypothyroidism, hyperthyroidism, subclinical thyroid disease, and thyroid autoimmunity. The search focused on diagnostic criteria, treatment modalities, and maternal and fetal complications associated with these conditions. Thyroid hormone demand increases during pregnancy, leading to physiological changes such as an increase in thyroid-binding globulin and changes in thyroid-stimulating hormone (TSH) levels. The prevalence of hypothyroidism in pregnancy ranges from 2-5%, with subclinical hypothyroidism being more common than overt hypothyroidism. Untreated hypothyroidism is associated with adverse outcomes, including preeclampsia, preterm birth, and neurodevelopmental delay in offspring. Hyperthyroidism, though less common (0.1-0.4%), can lead to complications such as miscarriage, intrauterine growth restriction, and preterm delivery. Autoimmune thyroid disease, particularly Hashimoto’s thyroiditis and Graves’ disease, is also a significant concern in pregnant women, with potential effects on both the mother and fetus. Early screening for thyroid dysfunction, particularly in women at high risk (e.g., those with a history of thyroid disease, type 1 diabetes, or other autoimmune conditions), is essential for timely intervention. Levothyroxine remains the treatment of choice for hypothyroidism, with dosing adjustments often needed as pregnancy progresses. For hyperthyroidism, antithyroid medications, such as propylthiouracil in the first trimester and methimazole thereafter, are generally recommended, with careful monitoring to avoid fetal complications. Thyroid dysfunction in pregnancy requires careful monitoring and treatment to prevent adverse maternal and fetal outcomes. A multidisciplinary approach involving obstetricians and endocrinologists is essential for the optimal management of thyroid disorders during pregnancy. Further research is warranted to refine screening guidelines and treatment protocols, particularly in subclinical thyroid disease.

Maternal diseases and congenital anomalies of the kidney and urinary tract in offspring: a cohort study

BackgroundCongenital anomalies of the kidneys and urinary tract (CAKUT) are the most common cause of prenatally diagnosed developmental malformation. This study aimed to assess the relationship between maternal diseases and CAKUT in offspring.MethodsThis retrospective study enrolled all pregnant women registered from January 2020 to December 2022 at one medical center. Medical information on maternal noncommunicable diseases, including obesity, hypertension, diabetes mellitus, kidney disease, hyperthyroidism, hypothyroidism, psychiatric disease, epilepsy, cancer, and autoimmune disease was collected. Based on the records of ultrasound scanning during the third trimester, the diagnosis was classified as isolated urinary tract dilation (UTD) or kidney anomalies. Multivariate logistic regression was performed to establish models to predict antenatal CAKUT.ResultsAmong the 19,656 pregnant women, perinatal ultrasound detected suspicious CAKUT in 114 (5.8/1000) fetuses, comprising 89 cases with isolated UTD and 25 cases with kidney anomalies. The risk of antenatal CAKUT was increased in the fetuses of mothers who experienced gestational diabetes, thyroid dysfunction, neuropsychiatric disease, anemia, ovarian and uterine disorders. A prediction model for isolated UTD was developed utilizing four confounding factors, namely gestational diabetes, gestational hypertension, maternal thyroid dysfunction, and hepatic disease. Similarly, a separate prediction model for kidney anomalies was established based on four distinct confounding factors, namely maternal thyroid dysfunction, gestational diabetes, disorders of ovarian/uterine, and kidney disease.ConclusionsIsolated UTD and kidney anomalies were associated with different maternal diseases. The results may inform the clinical management of pregnancy and highlight potential differences in the genesis of various subtypes of CAKUT.Graphical abstract

Genetic and Protein Expression Comparison of Tissues of Differing Embryonic Origin.

Non-syndromic Craniosynostosis (CS) has an unknown etiology. The overproduction of thyroid hormones (THs) during pregnancy known as maternal hyperthyroidism has been cited by the CDC as a potential cause of CS. Elucidation of the mechanism for TH induced CS may allow for the creation of a novel more suitable treatment option. There are several signaling pathways involved in the differentiation and development of the tissues of the skull such as, BMP, Ihh, and Wnt. Wnt signaling has been linked to the differentiation of both embryonic mesoderm as well as neural crest cells, from which the relevant tissues of the skull originate. The goal of this study is to quantify and compare genetic and protein expression of relevant Wnt signaling molecules and their target genes within the Sagittal and Coronal sutures. Beta-Catenin is a Wnt signaling molecule that acts as a transcription factor modulating the expression of genes such as Runx2 and Twist1. These genes were selected as they are known to be involved in cranial development. Sutures were collected from an avian model of induced thyrotoxicosis and analyzed using qRT-PCR and western blotting. Results of the qRT-PCR showed a significant downregulation in Runx2 and Twist1 expression in the coronal sutures with no change in Twist1 and a significant upregulation of Runx2 expression in the sagittal sutures. Western blot results are still pending. While further investigation into these pathways is necessary, our findings conclude that these key pathways react differently to modulation by thyroid hormones in tissues of differing embryonic origin.

Transient Hyperthyroidism of Hyperemesis Gravidarum: A Case Report from Rural Kenya

Purpose: The aim of the study was to assess the transient hyperthyroidism of hyperemesis gravidarum: A case report from rural Kenya.
 Materials and Methods: This study adopted a desk methodology. A desk study research design is commonly known as secondary data collection. This is basically collecting data from existing resources preferably because of its low cost advantage as compared to a field research. Our current study looked into already published studies and reports as the data was easily accessed through online journals and libraries.
 Findings: Hyperthyroidism complicates 0.2-0.4% of pregnancies. It may be diagnosed in the setting of hyperemesis gravidarum and can be pathological or transient. Untreated pathological hyperthyroidism has adverse maternal and fetal outcomes. Transient hyperthyroidism of hyperemesis gravidarum (THHG) affects up to 60% of women with hyperemesis, is self-limiting, and needs no antithyroid drug treatment. A diagnosis of THHG (rather than overt pathological hyperthyroidism) should be made when hyperthyroidism occurs in the setting of hyperemesis gravidarum and in the absence of pre-pregnancy hyperthyroidism, clinical findings compatible with maternal hyperthyroidism, and a negative antithyroid autoimmune profile. THHG resolves by the end of the first trimester without adverse pregnancy outcomes. We present a case from a rural Kenyan hospital to highlight the clinical profile and management of THHG for the primary care physician.
 Implications to Theory, Practice and Policy: Assessment of thyroid functions is indicated in hyperemesis gravidarum, where there are clinical features of hyperthyroidism. THHG is a self-limiting benign condition that may inappropriately lead to unnecessary drug treatment for pathological hyperthyroidism in pregnancy. A diagnosis of THHG should be made when a laboratory picture of hyperthyroidism occurs in the setting of hyperemesis gravidarum in the absence of pre-pregnancy hyperthyroidism, compatible physical findings, and a negative antithyroid autoantibody profile.

Environmental factors associated with incidence of developmental dysplasia of the hip: a systematic review and meta-analysis

BackgroundEstablished associated factors for DDH include female sex, breech presentation, family history, congenital malformations, oligohydramnios, and maternal hyperthyroidism. However, evidence for environmental factors that may contribute to DDH is limited and inconsistent.MethodsA systematic review of medical literature was conducted to collect data on environmental factors, including latitude, longitude, average yearly precipitation, average yearly temperature, minimum monthly temperature, and maximum monthly temperature, from all institutions that published articles on DDH. Univariate linear regression analysis was used to examine the correlation between environmental factors and DDH incidence, while multiple regression analysis was conducted to identify significant associated factors for DDH incidence.ResultsData from a total of 93 unique manuscripts were analyzed, revealing a significant negative correlation between DDH incidence and temperature, including average yearly temperature (r = -0.27, p = 0.008), minimum monthly temperature (r = -0.28, p = 0.006), and maximum monthly temperature (r = -0.23, p = 0.029). Additionally, there was a significant positive correlation between DDH incidence and latitude (r = 0.27, p = 0.009), and a significant negative correlation between DDH incidence and average yearly precipitation (r = -0.29, p = 0.004). In the final multiple regression analysis, temperature, including average yearly temperature, minimum monthly temperature, and maximum monthly temperature, were identified as significant associated factors for DDH incidence.ConclusionThe findings of this study suggest an association between cold weather and DDH incidence. Further research should explore the link between cold weather and DDH incidence, offering insights into potential interventions for cold climates.

Association of maternal thyroid disease with obesity in child

ObjectivesDuring pregnancy, many women develop thyroid disorders, which can result in fetal and neonatal development defects. We investigated whether maternal thyroid dysfunction would affect their children’s growth and obesity. Study designWe conducted a nationwide population-based cohort study using a combination of data from several Korean nationwide registries to investigate the association between maternal thyroid dysfunction, offspring growth, and obesity. Childhood growth was repeatedly measured at three periods of age from 42 to 80 months, using body mass index (BMI). ResultsA total of 1,123,499 women were enrolled in this study; 78,902 (7.0 %) had pre-pregnancy thyroid disease. Significant association was found between maternal hyperthyroidism and obesity in all children aged 42–66 months (42–54 months, adjusted odds ratio (aOR) 0.93, 95 % confidence interval (CI) 0.89–0.98; 54–66 months, aOR 0.93, 95 % CI 0.87–0.99), but not at later ages. In the analysis by sex, maternal hyperthyroidism was associated with childhood obesity in boys, whereas it was not associated with those in girls of any age. No association was observed between maternal hypothyroidism and child BMI or obesity. ConclusionsThe association between maternal thyroid function and obesity in offspring is attenuated from early to late childhood, suggesting that many other factors may be involved in developing childhood obesity.

Maternal thyroid hormone receptor β activation in mice sparks brown fat thermogenesis in the offspring

It is well established that maternal thyroid hormones play an important role for the developing fetus; however, the consequences of maternal hyperthyroidism for the offspring remain poorly understood. Here we show in mice that maternal 3,3’,5-triiodothyronine (T3) treatment during pregnancy leads to improved glucose tolerance in the adult male offspring and hyperactivity of brown adipose tissue (BAT) thermogenesis in both sexes starting early after birth. The activated BAT provides advantages upon cold exposure, reducing the strain on other thermogenic organs like muscle. This maternal BAT programming requires intact maternal thyroid hormone receptor β (TRβ) signaling, as offspring of mothers lacking this receptor display the opposite phenotype. On the molecular level, we identify distinct T3 induced alterations in maternal serum metabolites, including choline, a key metabolite for healthy pregnancy. Taken together, our results connect maternal TRβ activation to the fetal programming of a thermoregulatory phenotype in the offspring.

Iodine-induced thyroid dysfunction: a scientometric study and visualization analysis.

Iodine is essential in thyroid hormone production. Iodine deficiency is associated with serious complications (i.e miscarriage and stillbirth), whereas excess can cause thyroid dysfunction (i.e hyperthyroidism, hypothyroidism, thyroid autoimmunity). We conducted this scientometric study to visualize hot spots and trends in iodine-induced thyroid dysfunction over past two decades. The aim of this paper was to help scholars quickly understand the development and potential trend in this field, and guide future research directions. Articles on iodine-induced thyroid dysfunction from 2000 to 2022 were retrieved from the Web of Science Core Collection (WoSCC) using the following search terms: (((((TS=(hypothyroid*)) OR TS=(hyperthyroid*)) OR TS= ("TSH deficiency")) OR TS= ("thyroid stimulating hormone deficiency")) AND TS=(Iodine)) NOT TS=(radioiodine). Only publications in English were selected. CiteSpace, VOSviewer, Tableau, Carrot2, and R software were used to analyze the contribution and co-occurrence relationships of different countries, institutes, keywords, references, and journals. A total of 2986 publications from 115 countries and 3412 research institutions were included. From 2000 to 2022, research on iodine-induced thyroid dysfunction progressed over a three-stage development period: initial development (2000-2009), stable development (2010-2016), and rapid development (2016-2022) period. The Journal of Clinical Endocrinology and Metabolism had the most co-citations followed and China Medical University (n=76) had the most publications. The top three clusters of co-citation references were isolated maternal hypothyroxinemia, subclinical hyperthyroidism, and brain development. Various scientific methods were applied to reveal acknowledge structure, development trend and research hotspots in iodine-induced thyroid dysfunction. Our scientometric analysis shows that investigations related to pregnant women, epidemiology surveys, and iodine deficiency are promising topics for future iodine-induced thyroid dysfunction research and highlights the important role of iodine on thyroid function.

Unmasking the Culprit: Maternal Hyperthyroidism Presenting as Fetal Supraventricular Tachycardia and Hydrops

AbstractManagement of fetal supraventricular tachycardia at times can be tricky and challenging when they are secondary to underlying metabolic or hormonal problems. It can difficult to unmask the real culprit unless thorough evaluation is performed.

The Effect of Induced Thyrotoxicosis on Avian Limb Development.

Thyroid hormone (TH) is essential for bone development. Altered TH levels such as hyperthyroidism, or thyrotoxicosis, results in the early maturation of the cartilaginous scaffold for long bone development, which can cause improper ossification. Maternal hyperthyroidism during embryonic development causes neonatal thyrotoxicosis and can therefore lead to stunted growth in infants. In our avian model of induced thyrotoxicosis, we injected saline (control) or 25ng thyroxine (T4) in 0.1 mL dose into fertilized chicken eggs on embryonic (E) days E11 and E15. On E19, chicken embryo length was measured and limbs were collected. The left limbs were whole-mount stained with Alizarin Red (bone) and Alcian Blue (cartilage). Limbs were then imaged and tibias were measured using ImageJ. The tibias from the right limbs were further dissected, embedded in paraffin, cut (5μM), and stained with Safranin O (cartilage) and Fast Green (bone). Sections were examined to determine morphological changes in the cartilaginous long bone scaffold. Body length was 4.8% shorter following thyroxine exposure (p<0.01). Tibias were 2.4% shorter, though not statistically significant (p=0.36). Paraffin-embedded sections suggested increased chondrocyte hypertrophy, although further quantification is required. In conclusion, our data support thyroxine-induced changes in long bone morphology. Understanding how thyrotoxicosis can alter bone development in utero is important for developing potential targeted therapies for improving ossification in cases of neonatal thyrotoxicosis.
 
 Acknowledgment of NASA West Virginia Space Grant Consortium (Grant #80NSSC20M0055) and the Genomics Core Facility and WV-INBRE (NIH grant P20GM103434).

Validation of an Avian Model of Induced-Thyrotoxicosis

TYLER P. HILL, and HOLLY RACINE, Dept of Biomedical Science, West Liberty University, West Liberty, WV, 26074, Validation of an Avian Model of Induced-Thyrotoxicosis
 This project aimed to validate the avian model developed in our lab with the ultimate goal of discovering the potential link between maternal hyperthyroidism and craniosynostosis (CS). The method of validation for this model was to qualitatively measure the levels of thyroxine (T4) present in the treated embryos' systems at different time points post-injection. T4 was fluorescently labeled using Alexa fluorophore 488 and was injected into an experimental group of N=37 on embryonic day 11 (E11). Three control groups were used one N=9 Saline injected, another N=5 injected with the unconjugated free dye, and lastly, N=5 T4 injected only. The results showed that after 24 hours post-injection the fluorescent tag was present in the albumen with a peak at 72 hours, after 48 hours fluorescence is detected in the yolk with a peak at 96 hours, finally, after 72 hours there is a large peak in the blood before becoming undetectable at 96 hours. These trends suggest the injection is traveling from the injection site through these tissues and ultimately into the bloodstream, which is supported by the molecular assaying via ELISAs previously conducted. The results of this project in conjunction with the ELISA data show that the peaks detected are from injected T4 rather than a natural spike in development. Prior physiological data collected supports that the T4 injection not only makes its way into the bloodstream but also has a metabolic effect leading to changes in development. These results combined validate this model of induced thyrotoxicosis.
 (Supported by NIH Grant P20GM103434 to the West Virginia IDeA Network for Biomedical Research Excellence)
 Acknowledgment of NASA West Virginia Space Grant Consortium (Grant #80NSSC20M0055)

Induced Thyrotoxicosis Elicits Protective Effects in Developing Hearts

Maternal hyperthyroidism effects development in infants and can lead to conditions such as craniosynostosis, exophthalmos, and cardiac hypertrophy. Models for studying maternal hyperthyroidism, or thyrotoxicosis, are limited. Our lab has established an avian model to study the effects of induced thyrotoxicosis on embryonic development. Thyroid hormones (TH) cause inotropic and chronotropic changes in cardiac tissue, including increased cardiac output, increased blood volume, and hypertrophy. Therefore, we wanted to investigate the cardiac changes in our model. Fertilized chicken eggs are injected on embryonic days (E) 11 and 15 with either saline (control) or 25ng thyroxine (T4). Hearts were harvested on day E19, with halves of each sample used for histological staining with Masson’s Trichrome and qRT-PCR analysis. The main objective was to observe systemic effects of our model by studying morphological and genetic changes in the heart following exposure by measuring expression of THRa (TR receptor), ATP2A2 (calcium ATPases), and MYH7(Myosin heavy chain 7). We hypothesized that levels of all 3 markers would be upregulated, since THRaregulates transcription of these other cardiac markers due to fluctuating levels of TH. These are linked to ventricular hypertrophy when upregulated. However, our results contradicted our hypothesis. There was downregulation of all 3 genes, with a significant downregulation in ATP2A2. In combination with other data collected in our lab and related literature, we suspect that there is a cardiac protective effect occurring in the hearts following thyroxine exposure.

Differential morphometric analysis of the anterior fontanelle in an embryonic avian model of induced-thyrotoxicosis.

Craniosynostosis (CS) is the premature fusion of the cranial sutures during embryonic development, and this results in intracranial pressure and skull deformities. Thyrotoxicosis, specifically maternal hyperthyroidism, has been linked to the development of CS. Our lab is currently validating an avian model of thyroxine-induced CS to study the mechanism involved in thyroxine-enhanced cranial ossification. We hypothesized that thyroxine exposure will alter skull morphology. Two groups of fertilized chicken eggs were injected with saline or 25 ng T4 into the air cell on embryonic days (E) 11 and 15. A set of skulls from each group were collected on E17-19 (n = 17-21/day). They were fixed in formalin and processed using Alizarin Red whole-mount staining, imaged (superior view), and quantified to determine thyroxine-induced alteration in skull morphology. Geometric morphometric analysis using MorphoJ was performed to identify shape variation between treatment groups of the fibrous space between ossifying regions of the anterior fontanelle. These preliminary results demonstrated a significant variation in the shape of the fibrous gap between developing sutures on embryonic days 17, 18, and 19 (p<0.05). Using the same methodology, an additional set of skulls on E19 were collected from each group and processed using both Alizarin red and Alcian blue whole-mount staining to better delineate the ossifying region of bone. Analysis is currently in progress. In conclusion, these findings support that our model is successful in promoting the fusing of the cranial bones with thyroxine exposure in our avian model through altered skull morphology visualized in the anterior fontanelle.

Hyperthyroidism in pregnancy: design and methodology of a Danish multicenter study

BackgroundGraves’ disease (GD) is the main cause of hyperthyroidism in women of the fertile age. In pregnant women, the disease should be carefully managed and controlled to prevent maternal and fetal complications. Observational studies provide evidence of the adverse effects of untreated hyperthyroidism in pregnancy and have in more recent years substantiated a risk of teratogenic side effects with the use of antithyroid drugs (ATDs). These findings have challenged the clinical recommendations regarding the choice of treatment when patients become pregnant. To extend observational findings and support future clinical practice, a systematic collection of detailed clinical data in and around pregnancy is needed.MethodsWith the aim of collecting clinical and biochemical data, a Danish multicenter study entitled ‘Pregnancy Investigations on Thyroid Disease’ (PRETHYR) was initiated in 2021. We here describe the design and methodology of the first study part of PRETHYR. This part focuses on maternal hyperthyroidism and recruits female patients in Denmark with a past or present diagnosis of GD, who become pregnant, as well as women who are treated with ATDs in the pregnancy, irrespective of the underlying etiology. The women are included during clinical management from endocrine hospital departments in Denmark, and study participation includes patient questionnaires in pregnancy and postpartum as well as review of medical records from the mother and the child.ResultsData collection was initiated on November 1, 2021 and covered all five Danish Regions from March 1, 2022. Consecutive study inclusion will continue, and we here report the first status of inclusion. As of November 1, 2022, a total of 62 women have been included in median pregnancy week 19 (interquartile range (IQR): 10–27) with a median maternal age of 31.4 years (IQR: 28.5–35.1). At inclusion, 26 women (41.9%) reported current use of thyroid medication; ATDs (n = 14), Levothyroxine (n = 12).ConclusionThis report describes a newly established systematic and nationwide collection of detailed clinical data on pregnant women with hyperthyroidism and their offspring. Considering the course and relatively low prevalence of GD in pregnant women, such nationwide design is essential to establish a sufficiently large cohort.

Maternal hyperthyroidism alters the immunological mediators profile and population of natural killers cells in decidua of rats

Decidual immunological mediators modulate placental formation, decidualization and fetal development. However, the effect of maternal hyperthyroidism on decidual immunology needs further research. The aim of this study was to evaluate the population of uterine natural killer cells (uNKs) and the expression of immunological mediators in the decidua of female rats throughout pregnancy. Wistar rats were used and hyperthyroidism was induced by daily administration of L-thyroxine (T4) throughout pregnancy. The population of uNK cells in decidua was evaluated by immunostaining Lectin DBA, as well as the expression of interferon γ (INFγ), macrophage migration inhibitory factor (MIF), interleukin 15 (IL-15) and inducible nitric oxide synthase (iNOS) at 7, 10, 12, 14 and 19 days of gestation (DG). Maternal hyperthyroidism reduced the DBA+ uNK cell population in the decidua at 7 (P < 0.05) and 10 (P < 0.01) DGs compared to that in the control group, while it increased in the basal decidua (P < 0.05) and metrial gland (P < 0.0001) at the 12th DG. Hyperthyroidism also increased immunostaining of IL-15 (P < 0.0001), INFγ (P < 0.05), and MIF (P < 0.05) in the 7th DG, and increased immunostaining of IL-15 (P < 0.0001) and MIF (P < 0.01) in the 10th DG. However, excess thyroxine reduced IL-15 expression in the metrial gland and/or basal decidua in the 12th (P < 0.05), 14th (P < 0.01), and 19th (P < 0.001) DGs, as was also observed for INFγ in the basal decidua (P<0.001) and metrial gland (P < 0.0001) in the 12th DG. Regarding iNOS, an antiinflammatory cytokine, lower expression was observed in the basal decidua of hyperthyroid animals at 7 and 12 DGs (P < 0.05), whereas an increase occurred in the 10th DG (P < 0.05). These data demonstrate that maternal hyperthyroidism in female rats, particularly between 7 and 10 DGs, reduces the population of DBA+ uNKs in the decidua and increases the expression of inflammatory cytokines, suggesting a more proinflammatory environment in early pregnancy caused by this gestational disease.

Incidence of and Risk Factors for Neonatal Hypothyroidism Among Women with Graves' Disease Treated with Antithyroid Drugs Until Delivery.

Background: The incidence of neonatal hypothyroidism among newborns born to mothers with Graves' disease (GD) who continued antithyroid drug (ATD) treatment until delivery has never been reported. Objective: Our primary objective was to investigate the incidence of neonatal hypothyroidism among newborns born to mothers with GD who were treated with ATD until delivery. Our secondary objective was to identify the cutoff ATD daily doses for neonatal hypothyroidism risk, based on maternal thyrotropin (TSH) receptor antibody (TRAb) levels. Methods: We conducted a retrospective cohort study. We included 305 pregnant women with GD who were treated with an ATD until delivery (63 treated with methimazole [MMI] and 242 treated with propylthiouracil [PTU]). Umbilical cord TSH, free thyroxine (fT4), and TRAb levels were measured at delivery, and we investigated the respective relationships between neonatal hypothyroidism at delivery and maternal fT4 levels, TRAb levels, and daily ATD doses during pregnancy. Neonatal hypothyroidism was diagnosed when the umbilical cord fT4 level was below the lower limit of the reference range. Results: The incidence of neonatal hypothyroidism at delivery was 19.0% ([confidence interval, CI, 11.2-30.4]; 12/63) in the MMI group and 12.8% ([CI, 9.2-17.6]; 31/242) in the PTU group. Neonatal goiter was observed in one neonate in the PTU group, and two infants in the PTU group required levothyroxine treatment. The daily ATD dose in the third trimester was the strongest predictor of neonatal hypothyroidism at delivery; the cutoff MMI dose was 10 mg/day, and the cutoff PTU dose was 150 mg/day. When the maternal TRAb level in the third trimester was above three times the upper limit of the normal range, the cutoff MMI dose was 20 mg/day, and the cutoff PTU dose was 150 mg/day. Conclusions: Maternal fT4 and TRAb levels were higher in the neonatal hypothyroid group, which suggested prolonged GD activity. Careful follow-up is necessary when maternal GD remains active and the ATD dose to control maternal thyrotoxicosis cannot be reduced.

Maternal hyperthyroidism increases the synthesis activity and the osteogenic markers expression of calvarial osteoblasts from offspring in a murine model

To evaluate the characteristics and synthesis activity of osteoblasts extracted from the calvaria of offspring of rats exposed to maternal hyperthyroidism. Twelve adult Wistar rats were divided into two groups, one control and one treated with daily administration of L-thyroxine by an orogastric tube (50 µg/animal/day) during pregnancy. Three days after delivery and confirmation of the mothers’ hyperthyroidism, the offspring were euthanized for the extraction of osteoblasts from the calvaria. At 7, 14, and 21 days, proliferation activity was assessed using MTT assay, while alkaline phosphatase (ALP) activity was assessed by the BCIP/NBT method. At 21 days, the total area of the mineralized matrix stained by von Kossa was evaluated by morphometry. The expression of gene transcripts for Runx2, Bmp2, Fgfr1, collagen type 1 (Col1), osteocalcin (Oc), and osteopontin (Op) were evaluated by real-time RT-PCR. Means were compared using the Student’s t-test. FA activity was significantly higher at 14 and 21 days in cultures of osteoblasts extracted from offspring exposed to maternal hyperthyroidism, while MTT conversion was significantly lower at 21 days in this group. Osteoblast cultures of neonates exposed to maternal hyperthyroidism also showed a larger total area of mineralized matrix and greater expression of gene transcripts for Oc and Op. Maternal hyperthyroidism increases the activity of matrix synthesis, alkaline phosphatase activity, and expression of gene transcripts for osteocalcin and osteopontin in the osteoblasts, extracted from the calvaria of the offspring, which may be one of the mechanisms of premature fusion of cranial sutures.

Neonatal Outcomes of Pregnancies Complicated by Maternal Hyperthyroidism.

This study aimed to determine the proportion, clinical characteristics, hormonal status, median time for normalization of serum thyroxine (FT4) and thyroid-stimulating hormone (TSH) and factors affecting time to thyroid function test (TFT) normalization of neonates born to mothers with maternal hyperthyroidism admitted in our institution. This was a retrospective cohort study that included 170 newborns admitted to the Neonatal Intensive Care Unit (NICU) of Hospital Universiti Sains Malaysia (HUSM) with a history of maternal hyperthyroidism from January 2013 until December 2018. We analyzed their baseline demographic and clinical characteristics, maternal thyroid status and antibody levels. Finally, we analyzed newborn thyroid function and thyroid antibodies. The proportion of neonates born to mothers with maternal hyperthyroidism was 0.8% (170 of 20,198 neonates within the study period). Seven (4.1%) developed overt hyperthyroidism, while four (2.4%) had thyroid storm. The median time for thyroid function test normalization was 30 days (95% CI: 27.1 to 32.8). The median time for TFT normalization was longer among neonates of mothers with positive thyroid antibodies [46.6 days (95% CI, 20.6 to 39.4)] and of mothers who received anti-thyroid treatment [31.7 days (95% CI, 23.5 to 39.9)]. Neonates born to mothers with hyperthyroidism is uncommon. These babies were observed to have a longer time for normalization of thyroid function tests if their mothers had thyroid antibodies or received anti-thyroid treatment.

DIO3 protects against thyrotoxicosis-derived cranio-encephalic and cardiac congenital abnormalities.

Maternal hyperthyroidism is associated with an increased incidence of congenital abnormalities at birth, but it is not clear which of these defects arise from a transient developmental excess of thyroid hormone and which depend on pregnancy stage, antithyroid drug choice, or unwanted subsequent fetal hypothyroidism. To address this issue, we studied a mouse model of comprehensive developmental thyrotoxicosis secondary to a lack of type 3 deiodinase (DIO3). Dio3-/- mice exhibited reduced neonatal viability on most genetic backgrounds and perinatal lethality on a C57BL/6 background. Dio3-/- mice exhibited severe growth retardation during the neonatal period and cartilage loss. Mice surviving after birth manifested brain and cranial dysmorphisms, severe hydrocephalus, choanal atresia, and cleft palate. These abnormalities were noticeable in C57BL/6J Dio3-/- mice at fetal stages, in addition to a thyrotoxic heart with septal defects and thin ventricular walls. Our findings stress the protecting role of DIO3 during development and support the hypothesis that human congenital abnormalities associated with hyperthyroidism during pregnancy are caused by transient thyrotoxicosis before clinical intervention. Our results also suggest thyroid hormone involvement in the etiology of idiopathic pathologies including cleft palate, choanal atresia, Chiari malformations, Kaschin-Beck disease, and Temple and other cranio-encephalic and heart syndromes.

Maternal subclinical hyperthyroidism and adverse pregnancy outcomes considering the iodine status: Tehran thyroid and pregnancy study

BackgroundUnlike overt thyroid diseases, the impacts of subclinical thyroid dysfunction, especially subclinical hyperthyroidism (SH), on adverse pregnancy outcomes are inconclusive. ObjectiveWe aimed to investigate the effect of maternal SH on adverse maternal and neonatal outcomes based on urinary iodine concentration (UIC). MethodsA secondary analysis was run on data collected in the Tehran Thyroid and Pregnancy study (TTPs). We used the data of 131 women with SH and 1650 cases of euthyroid. Serum levels of thyroid-stimulating hormone (TSH), thyroxine (T4), free thyroxine index (FT4I), and thyroid peroxidase antibody (TPOAb) were assessed at the first prenatal visit. A generalized linear regression model was applied to identify the effect of SH on the pregnancy outcomes based on UIC, and the effects were estimated with a 95% confidence interval. ResultsPreterm delivery was observed in 12.3% of women with SH and 6.7% of those with euthyroid (P = 0.03). Women with TSH< 0.3 mIU/L had a higher odds of preterm delivery than those with TSH≥ 0.3 regardless of urine iodine cut-off [OR= 2.27; 95% CI: (1.15, 4.48), p = 0.02]. Among those with UIC levels≥ 150 μg/L, the odds ratio of preterm delivery was 4.61 folds higher in the SH group compared to those with euthyroid [95%CI: (1.36, 15.71), p = 0.01)]. No significant difference between these two study groups was found in Neonatal Intensive Care Unit admission. Moreover, the results revealed no statistically significant difference in the means of neonatal anthropometric parameters in the SH and euthyroid groups in none of the subgroups of UIC (<150 or ≥150 µg/l). ConclusionsAccording to our results, maternal SH appears to be a risk factor for preterm delivery. This effect is more pronounced in women with higher UIC than those with lower UIC.