OBJECTIVE: Levothyroxine (LEV) monotherapy cannot completely improve cognitive and behavioral impairments induced by hypothyroidism, whereas a combination therapy of exercise and LEV may ameliorate these deficits. This study aimed to determine the effects of mild-intensity forced exercise and LEV treatment on the anxiety profile and cognitive functions in male offspring of hypothyroid dams.
METHODS: Twenty-four female rats (mothers) were randomly divided into sham (healthy) and hypothyroidism groups and then placed with male rats to mate. The presence of vaginal plaque confirmed pregnancy (gestational day, GD 0). 6-propyl-2-thiouracil (PTU, 100 ppm) was added to the drinking water of the hypothyroidism group from GD 6 to the 21st postnatal day (PND). The sham group received tap water. On PND 21, serum T4 levels of mothers, and 10 pups were measured to confirm hypothyroidism. Sixty-four male pups were left undisturbed for 30 days and then were divided into eight groups that received saline or LEV (50 μg/kg, i.p.) with or without forced mild-intensity exercise. After 14 days of interventions, anxiety-like behaviors, spatial learning and memory, and hippocampal brain-derived neurotrophic factor (BDNF) levels were evaluated.
RESULTS: A pre and postnatal PTU-induced model of hypothyroidism increased anxiety-like behaviors, impaired spatial learning and memory, and decreased hippocampal BDNF levels in male offspring rats. LEV alone increased BDNF levels and improved spatial learning. Exercise alone increased BDNF levels, improved spatial learning and memory, and decreased anxiety-like behaviors. Exercise plus LEV more effectively improved anxiety-like behaviors and spatial learning than exercise or LEV alone.
CONCLUSIONS: Practically, these pre-clinical findings highlight the importance of the combination of exercise and LEV regimen in treating patients with hyperthyroidism.

Hypothyroidism, a prevalent endocrine disorder, carries significant implications for maternal and infant health, especially in the context of maternal hypothyroidism. Despite a gradual surge in recent research, achieving a comprehensive understanding of the current state, focal points, and developmental trends in this field remains challenging. Clarifying these aspects and advancing research could notably enhance maternal-infant health outcomes. Therefore, this study employs bibliometric methods to systematically scrutinize maternal hypothyroidism research, serving as a reference for further investigations.
Through bibliometric analysis, this study seeks to unveil key research focus areas, developmental trends, and primary contributors in Maternal Hypothyroidism. The findings offer insights and recommendations to inform future research endeavors in this domain.
Literature metrics analysis was performed on data retrieved and extracted from the Web of Science Core Collection database. The analysis examined the evolution and thematic trends of literature related to Maternal Hypothyroidism. Data were collected on October 28, 2023, and bibliometric analysis was performed using VOSviewer, CiteSpace, and the Bibliometrix software package, considering specific characteristics such as publication year, country/region, institution, authorship, journals, references, and keywords.
Retrieved from 1,078 journals, 4,184 articles were authored by 18,037 contributors in 4,580 institutions across 113 countries/regions on six continents. Maternal Hypothyroidism research publications surged from 44 to 310 annually, a 604.54% growth from 1991 to 2022. The USA (940 articles, 45,233 citations), China Medical University (82 articles, 2,176 citations), and Teng, Weiping (52 articles, 1,347 citations) emerged as the most productive country, institution, and author, respectively. \"Thyroid\" topped with 233 publications, followed by \"Journal of Clinical Endocrinology & Metabolism\" (202) with the most citations (18,513). \"Pregnancy\" was the most cited keyword, with recent high-frequency keywords such as \"outcome,\" \"gestational diabetes,\" \"iodine intake,\" \"preterm birth,\" \"guideline,\" and \"diagnosis\" signaling emerging themes in Maternal Hypothyroidism.
This study unveils developmental trends, global collaboration patterns, foundational knowledge, and emerging frontiers in Maternal Hypothyroidism. Over 30 years, research has predominantly focused on aspects like diagnosis, treatment guidelines, thyroid function during pregnancy, and postpartum outcomes, with a central emphasis on the correlation between maternal and fetal health.

The mother\'s thyroid hormone status during gestation and the first few months after delivery can play a crucial role in maturation during the brain development of the child. Transient abnormalities in thyroid function at birth indicate developmental and cognitive disorders in adulthood. Choline supplementation during gestation and the perinatal period in rats causes long-lasting memory improvement in the offspring. However, it remains unclear whether choline is able to restore the deficits in rats with maternal hypothyroidism. The aim of this study was to evaluate the effects of choline supplementation on the alteration of cognitive-behavioral function, long-term potentiation (LTP), and morphological changes as well as apoptosis in pre-pubertal offspring rats. To induce hypothyroidism, 6-propyl-2-thiouracil was added to the drinking water from the 6th day of gestation to the 21st postnatal day (PND). Choline treatment was started twice a day on the first day of the gestation until PND 21 via gavage. LTP recording and Morris water maze (MWM) test were conducted at PND 28. Then, the rats were sacrificed to assess their brains. The results revealed that developmental thyroid hormone deficiency impaired spatial learning and memory and reduced LTP (both: P < 0.001). Choline treatment alleviated LTP (P < 0.001), as well as learning and memory deficits (P < 0.01) in both male and female hypothyroid rats. However, no significant changes were observed in the number of caspase-3 stained cells in choline-receiving hypothyroid groups. The results revealed that developmental thyroid hormone deficiency impaired spatial learning and memory and reduced LTP. Choline treatment alleviated LTP, as well as learning and memory deficits in both male and female hypothyroid rats.

OBJECTIVE: To evaluate fetal cardiac function in cases with overt and subclinical hypothyroidism and to determine the effect of levothyroxine (LT4) treatment and Anti-thyroid peroxidase (Anti-TPO) antibody status on fetal cardiac functions in cases with subclinical hypothyroidism.
METHODS: Within the scope of the study, fetuses of 23 overt hypothyroid, 52 subclinical hypothyroid and 250 control group pregnant women were evaluated. Fetal cardiac function was assessed via cardiac Doppler.
RESULTS: Isovolumetric relaxation time (IRT) and myocardial performance index (MPI) values in the overt hypothyroid group were significantly higher than both the subclinical hypothyroid group (p: .006, p: .000, respectively) and the control group (p: .000, p: .000, respectively). In addition, both IRT and MPI were significantly higher in the subclinical hypothyroid group than in the control group (p: .000, p: .000, respectively). In the subclinical hypothyroid group, there was no significant difference in terms of cardiac function parameters in the fetuses of pregnant women who received LT4 therapy and those who did not. When pregnant women with subclinical hypothyroidism were evaluated according to their Anti-TPO antibody status, IRT and MPI values were found to be significantly higher in fetuses of Anti-TPO (+) pregnant women (respectively, p: .005, p: .019).
CONCLUSIONS: In the presence of maternal overt or subclinical hypothyroidism, fetal cardiac functions may be affected as early as the second trimester. Anti-TPO antibody positivity in cases with subclinical hypothyroidism seems to negatively affect fetal cardiac functions.

Maternal hypothyroidism (MH) could adversely affect the cardiac disease responses of the progeny. This study tested the hypothesis that MH reduces early postnatal cardiomyocyte (CM) proliferation so that the adult heart of MH progeny has a smaller number of larger cardiac myocytes, which imparts adverse cardiac disease responses following injury. Thyroidectomy (TX) was used to establish MH. The progeny from mice that underwent sham or TX surgery were termed Ctrl (control) or MH (maternal hypothyroidism) progeny, respectively. MH progeny had similar heart weight (HW) to body weight (BW) ratios and larger CM size consistent with fewer CMs at postnatal day 60 (P60) compared with Ctrl (control) progeny. MH progeny had lower numbers of EdU+, Ki67+, and phosphorylated histone H3 (PH3)+ CMs, which suggests they had a decreased CM proliferation in the postnatal timeframe. RNA-seq data showed that genes related to DNA replication were downregulated in P5 MH hearts, including bone morphogenetic protein 10 (Bmp10). Both in vivo and in vitro studies showed Bmp10 treatment increased CM proliferation. After transverse aortic constriction (TAC), the MH progeny had more severe cardiac pathological remodeling compared with the Ctrl progeny. Thyroid hormone (T4) treatment for MH mothers preserved their progeny\'s postnatal CM proliferation capacity and prevented excessive pathological remodeling after TAC. Our results suggest that CM proliferation during early postnatal development was significantly reduced in MH progeny, resulting in fewer CMs with hypertrophy in adulthood. These changes were associated with more severe cardiac disease responses after pressure overload.NEW & NOTEWORTHY Our study shows that compared with Ctrl (control) progeny, the adult progeny of mothers who have MH (MH progeny) had fewer CMs. This reduction of CM numbers was associated with decreased postnatal CM proliferation. Gene expression studies showed a reduced expression of Bmp10 in MH progeny. Bmp10 has been linked to myocyte proliferation. In vivo and in vitro studies showed that Bmp10 treatment of MH progeny and their myocytes could increase CM proliferation. Differences in CM number and size in adult hearts of MH progeny were linked to more severe cardiac structural and functional remodeling after pressure overload. T4 (synthetic thyroxine) treatment of MH mothers during their pregnancy, prevented the reduction in CM number in their progeny and the adverse response to disease stress.

Concerns have been raised regarding thyroid dysfunction in infants born to women with hypothyroidism including those with autoimmune hypothyroidism. This concern has led to the practice of thyroid function testing in the early neonatal period. We evaluated the practice of performing a routine thyroid function test around 2 weeks of age in all healthy full-term infants (≥37 weeks gestation) born to women with hypothyroidism to identify thyroid dysfunction.
This retrospective, observational single centre study included full-term infants born to women with hypothyroidism, including non-Graves\' autoimmune hypothyroidism, over a 3-year period. Preterm infants and those born to women with Graves\' disease or thyroidectomy were excluded.
Of the 790 mother-infant dyads, 780 infants (99%) had normal thyroid function. Only 10 infants (1%) had thyroid stimulating hormone (TSH) levels > 10mIU/L at 2 weeks of age (range 10.25-106.37 mU/L). Of these, follow-up thyroid function normalized in nine infants within 2 weeks. A routine newborn screening test identified congenital hypothyroidism in one infant. No infant born to women with known presence of anti-thyroid antibodies had TSH levels > 10 mIU/L. Thyroid function was normal for most infants where maternal anti-thyroid antibodies were not known (125/133, 94%).
Infants born to women with hypothyroidism (including autoimmune hypothyroidism) had normal thyroid function in the early neonatal period. A small proportion of infants may develop TSH levels > 10 mU/L that normalizes by 4 weeks of age. The practice of routine thyroid function testing for this cohort in addition to newborn screening test offers no additional benefit.

OBJECTIVE: In this study, we investigated whether maternal hypothyroidism has a role in the cardiac output (CO) of the fetus or not.
METHODS: Pregnant women between 33 and 37 gestational weeks known to have hypothyroidism and using levothyroxine were accepted as the case group. Gestational age-matched healthy euthyroid pregnant women constituted the control group. Fetal echocardiography was performed. Diameters and the velocity waveform of the pulmonary artery (PA) and aortic valves were measured. Velocity time integral (VTI) was also measured from the ventricular outflow tract. CO was calculated using VTI × π (Aortic Valve or Pulmonary Valve diameter/2) 2 × heart rate formula.
RESULTS: The aortic and PA annulus were measured larger in the control group. (p = .003, p = .005, respectively). Furthermore, the right and left CO of the case group were lower than the control group. Whereas the mean combined CO (ml/min) of the case group was 674.8 ± 146.2, it was 827.8 ± 167.9 in the control group (p < .001). Additionally, a negative correlation was observed between thyroid-stimulating hormone and aortic VTI (r:-.480; p:.006).
CONCLUSIONS: The findings of our study suggest that the CO of the fetus may be affected by maternal hypothyroidism.

Thyroid hormones are critical for the development of opsins involved in color vision. Hypothyroid mice show delayed M-opsin development and expanded distribution of S-opsin on the retina. However, the effects of maternal hypothyroidism on opsin development remain unknown. This study investigates the effects of congenital central hypothyroidism and maternal hypothyroidism on opsin development in thyrotropin-releasing hormone knockout (TRH-/-) mice. We examined the mRNA expression and protein distribution of S/M-opsin on postnatal days (P)12 and 17, as well as mRNA expression of type 2 and 3 iodothyronine deiodinase (DIO2 and DIO3, respectively) in the retina and type 1 iodothyronine deiodinase (DIO1) in the liver at P12 in TRH+/- mice born to TRH+/- or TRH-/- dams, and conducted S/M-opsin analysis in TRH+/+ or TRH-/- mice born to TRH+/- dams at P12, P17, and P30. M-opsin expression was lower in TRH+/- mice born to TRH-/- dams than in those born to TRH+/- dams, whereas S-opsin expression did not significantly differ between them. DIO1, DIO2, and DIO3 mRNA expression levels were not significantly different between the two groups; therefore, thyroid function in peripheral tissues in the pups was similar. S/M-opsin expression did not significantly differ between the TRH+/+ and TRH-/- mice born to TRH+/- dams on any postnatal day. These results demonstrate that maternal hypothyroidism causes M-opsin developmental delay during the early developmental stages of neonatal mice, and TRH-/- mice, a model of congenital central hypothyroidism, born to a euthyroid dam do not have delayed opsin development.

BACKGROUND: Antenatal/early postnatal hypothyroidism weakens NO-mediated anticontractile influence of endothelium in coronary arteries of adult rats, but it remains unclear whether this occurs in other vascular regions. We hypothesized that developmental thyroid deficiency is followed by region-specific changes in the endothelial NO-pathway activity in systemic vasculature. To explore this, we estimated the effects of antenatal/early postnatal hypothyroidism on NO-pathway activity and its potential local control mechanisms in rat mesenteric and skeletal muscle (sural) arteries.
METHODS: Dams were treated with 6-propyl-2-thiouracil (PTU) in drinking water (0.0007%) during pregnancy and 2 weeks postpartum; control (CON) females received PTU-free water. Adult offspring (10-12-weeks) arteries were studied by wire myography, qPCR, and Western blotting.
RESULTS: Endothelium removal or inhibition of NO-synthase with L-NNA augmented contractile responses to α1-adrenoceptor agonist methoxamine. In PTU compared to CON group, these effects were stronger in sural arteries, but did not differ in mesenteric arteries. The responses of both arteries to NO-donor DEA/NO were similar in CON and PTU rats. mRNA contents of deiodinase 2 and thyroid hormone receptor α were similar in mesenteric arteries of two groups but were elevated in sural arteries of PTU group compared to CON. The abundance of eNOS protein was higher in sural arteries of PTU compared to CON rats.
CONCLUSIONS: Antenatal/early postnatal hypothyroidism is followed by an increase in NO-mediated anticontractile influence in sural, but not in mesenteric arteries of adult animals. The diversity of hypothyroidism effects may be due to different alterations of local T3 synthesis/reception in different vascular beds.

OBJECTIVE: Pregnancy is a critical period keenly regulated by both maternal and foetal factors and a shift in these factors could result in severe complications manifesting in foetal and adult life. However, maternal hypothyroidism before and/or during pregnancy is a critical factor. This study investigated the effect of maternal hypothyroidism on glucose tolerance and thyroid function in male and female offspring.
METHODS: Fifteen adult female Wistar rats were divided into three groups: Group 1 (sham-control), Group 2 (thyrodectomized) and Group 3 (thyroidectomised + L-thyroxine treated). Blood thyroxine (T4) level was measured on the day 10 after thyroidectomy in Groups 1 and 2, and day 35 in Group 3. Males were introduced to the female rats after T4 measurement. At PND-112, T4 levels of their offspring were measured. Oral Glucose Tolerance Test (OGTT) was measured in offspring at PND-133.
RESULTS: Thyroxine reduced significantly in Group 2 and their offspring (male and female) compared to Group 3 while gestation period was prolonged significantly in Group 2 compared to Group 1. Hypothyroid male offspring showed depressed glucose tolerance, however, no effect was observed in female offspring.
CONCLUSIONS: This study suggests that maternal hypothyroidism prolonged gestation period, induced foetal hypothyroidism in both genders and depressed glucose tolerance in male offspring.