Pregnancy-related hormonal changes and thyroid growth: do they have an impact on the higher incidence of differentiated thyroid cancer in women?

PURPOSE OF REVIEW: To analyze whether pregnancy could play a role in the higher prevalence of differentiated thyroid carcinoma (DTC) in women. Estrogens strongly modify thyroid economy by increasing iodine clearance, thyroid hormone requirement and production. Human chorionic gonadotropin (hCG) contributes to the increased thyroid hormone synthesis. Both estrogens and hCG can interfere with the regulation of thyroid volume and with thyroid nodule development and progression. The potential effect of hCG is exclusively related to its weak agonistic activity on TSH receptor. Estrogen implication on normal and nodule-derived thyrocyte growth has been demonstrated in vitro and in animal models. Furthermore, there is solid clinical evidence showing a promoting effect of pregnancy on thyroid volume and nodule development. Two metanalysis, one including retrospective and another prospective observational studies, failed to show an association between pregnancy and DTC. RECENT FINDINGS: A large pooled prospective analysis using multivariable-adjusted Cox proportional hazard models did not demonstrate an association between DTC and parity. Similarly, no association between PTC occurrence and parity was observed in a prospective cohort analysis by linkage to the statewide Surveillance, Epidemiology, and End Results (SEER). SUMMARY: The presently available evidence does not support an involvement of pregnancy in DTC etiology.

Obstructive sleep apnea is not associated with diabetic retinopathy in diabetes: a prospective case-control study.

PURPOSE: Diabetic retinopathy (DR) is the most common ocular complication of type 2 diabetes mellitus (T2D) and is associated with diabetes duration, glycemic control, and hypertension (HTN). Obstructive sleep apnea (OSA) is frequent in T2D and is associated with poor glycemic control. However, it is unclear if there is an association between OSA and DR. This study aimed to assess whether or not the presence of OSA in patients with T2D was associated with DR. METHODS: In this prospective case-control study, consecutive patients with DM attending the ophthalmology clinics were recruited to include patients with DR (cases) and without DR (controls). OSA was diagnosed by attended polysomnography (PSG). Blood pressure and a fasting morning blood sample, including glycosylated hemoglobin (HbA1c), were recorded. Patients were matched for age, body mass index (BMI), gender, and T2D duration. RESULTS: Thirty diabetic patients with DR were matched with 30 controls. In all patients, the prevalence of moderate-to-severe OSA was 57%. In the logistic regression analysis, DR was associated with increased HbA1c (OR 2.63, 95% CI 1.35-5.16, p = 0.004) but not with any PSG parameter. In the DR group, PSG parameters were not associated with the severity of ocular disease (non-proliferative, proliferative, presence/absence of macular edema). The proliferative aspect of DR was correlated with age (p = 0.017). DR occurred more frequently in uncontrolled diabetes compared to well-controlled diabetes (80% vs 38%, p = 0.029). CONCLUSIONS: In patients with T2D, the presence of DR is not associated with OSA, but with poorly controlled T2D.

Update on therapeutic use of levothyroxine for the management of hypothyroidism during pregnancy.

Hypothyroidism is a relatively common finding during pregnancy. This may be due either to the presence of existing thyroid disease and/or to the increased demands that pregnancy places the thyroid gland to provide thyroid hormones for the mother and the developing fetus. There is no doubt that overt hypothyroidism is associated strongly with adverse pregnancy outcomes, including miscarriage. Meta-analyses show that thyroid hormone replacement with levothyroxine (LT4) reduces the risk of adverse pregnancy outcomes in the setting of overt hypothyroidism. Accordingly, management guidelines in this area are unanimous in recommending intervention with to control the level of thyrotropin (TSH) to below 2.5 µIU/mL. The evidence for an adverse impact of subclinical hypothyroidism (SCH) on pregnancy outcomes is less clear, although meta-analyses suggest that SCH reduces the chance of a successful pregnancy outcome. Guidelines also support intervention for some patients with SCH, particularly where TSH is high (>10 µIU/mL), or where TSH is above its trimester-specific reference range in a woman with thyroid autoimmunity (giving LT4 to euthyroid women with thyroid autoimmunity is not supported). Real-world evidence suggests that hypothyroidism in pregnancy is often overlooked or that LT4 is not given appropriately to gain tight control of TSH. More research is needed to identify the barriers to optimal thyroid care with LT4 at this crucial time.

Long-term hypothyroidism in patients started on levothyroxine during pregnancy.

Background: Current guidelines recommend different postpartum approaches for patients started on levothyroxine (LT4) during pregnancy. Objective: We studied the postpartum management of these patients and determined factors associated with long-term hypothyroidism. Methods: A retrospective study was conducted at a tertiary center between 2014 and 2020, with LT4 initiation according to 2014 ETA recommendations. We performed multivariate logistic regression (MVR) and a receiver operating characteristic curve analysis to determine variables associated with long-term hypothyroidism and their optimal cutoffs. Results: LT4 was initiated in 177 pregnant women, and 106/177 (60%) were followed at long-term (at least 6 months post partum) (28.5 (9.0-81.9) months). LT4 could have been stopped in 45% of patients who continued it immediately after delivery. Thirty-six out of 106 (34%) patients were long-term hypothyroid. In them, LT4 was initiated earlier during pregnancy than in euthyroid women (11.7 ± 4.7 vs 13.7 ± 6.5 weeks, P = 0.077), at a higher thyroid-stimulating hormone (TSH) level (4.1 (2.2-10.1) vs 3.5 (0.9-6.9) mU/L, P = 0.005), and reached a higher dose during pregnancy (62.8 ± 22.2 vs 50.7 ± 13.9 µg/day, P = 0.005). In the MVR, only the maximal LT4 dose during pregnancy was associated with long-term hypothyroidism (odds ratio (OR) = 1.03, 95% CI: 1.00-1.05, P = 0.003). The optimal cutoffs for predicting long-term hypothyroidism were an LT4 dose of 68.75 µg/day (87% specificity, 42% sensitivity; P = 0.013) and a TSH level ≥ 3.8 mU/L (68.5% specificity, 77% sensitivity; P = 0.019). Conclusion: One-third of the patients who started on LT4 during pregnancy had long-term hypothyroidism. The TSH level at treatment initiation and the LT4 dose during pregnancy could guide the decision for continuing long-term LT4.

TSH and FT4 Reference Interval Recommendations and Prevalence of Gestational Thyroid Dysfunction: Quantification of Current Diagnostic Approaches.

CONTEXT: Guidelines recommend use of population- and trimester-specific thyroid-stimulating hormone (TSH) and free thyroxine (FT4) reference intervals (RIs) in pregnancy. Since these are often unavailable, clinicians frequently rely on alternative diagnostic strategies. We sought to quantify the diagnostic consequences of current recommendations. METHODS: We included cohorts participating in the Consortium on Thyroid and Pregnancy. Different approaches were used to define RIs: a TSH fixed upper limit of 4.0 mU/L (fixed limit approach), a fixed subtraction from the upper limit for TSH of 0.5 mU/L (subtraction approach) and using nonpregnancy RIs. Outcome measures were sensitivity and false discovery rate (FDR) of women for whom levothyroxine treatment was indicated and those for whom treatment would be considered according to international guidelines. RESULTS: The study population comprised 52 496 participants from 18 cohorts. Compared with the use of trimester-specific RIs, alternative approaches had a low sensitivity (0.63-0.82) and high FDR (0.11-0.35) to detect women with a treatment indication or consideration. Sensitivity and FDR to detect a treatment indication in the first trimester were similar between the fixed limit, subtraction, and nonpregnancy approach (0.77-0.11 vs 0.74-0.16 vs 0.60-0.11). The diagnostic performance to detect overt hypothyroidism, isolated hypothyroxinemia, and (sub)clinical hyperthyroidism mainly varied between FT4 RI approaches, while the diagnostic performance to detect subclinical hypothyroidism varied between the applied TSH RI approaches. CONCLUSION: Alternative approaches to define RIs for TSH and FT4 in pregnancy result in considerable overdiagnosis and underdiagnosis compared with population- and trimester-specific RIs. Additional strategies need to be explored to optimize identification of thyroid dysfunction during pregnancy.

Defining Gestational Thyroid Dysfunction Through Modified Nonpregnancy Reference Intervals: An Individual Participant Meta-analysis.

BACKGROUND: Establishing local trimester-specific reference intervals for gestational TSH and free T4 (FT4) is often not feasible, necessitating alternative strategies. We aimed to systematically quantify the diagnostic performance of standardized modifications of center-specific nonpregnancy reference intervals as compared to trimester-specific reference intervals. METHODS: We included prospective cohorts participating in the Consortium on Thyroid and Pregnancy. After relevant exclusions, reference intervals were calculated per cohort in thyroperoxidase antibody-negative women. Modifications to the nonpregnancy reference intervals included an absolute modification (per .1 mU/L TSH or 1 pmol/L free T4), relative modification (in steps of 5%) and fixed limits (upper TSH limit between 3.0 and 4.5 mU/L and lower FT4 limit 5-15 pmol/L). We compared (sub)clinical hypothyroidism prevalence, sensitivity, and positive predictive value (PPV) of these methodologies with population-based trimester-specific reference intervals. RESULTS: The final study population comprised 52 496 participants in 18 cohorts. Optimal modifications of standard reference intervals to diagnose gestational overt hypothyroidism were -5% for the upper limit of TSH and +5% for the lower limit of FT4 (sensitivity, .70, CI, 0.47-0.86; PPV, 0.64, CI, 0.54-0.74). For subclinical hypothyroidism, these were -20% for the upper limit of TSH and -15% for the lower limit of FT4 (sensitivity, 0.91; CI, 0.67-0.98; PPV, 0.71, CI, 0.58-0.80). Absolute and fixed modifications yielded similar results. CIs were wide, limiting generalizability. CONCLUSION: We could not identify modifications of nonpregnancy TSH and FT4 reference intervals that would enable centers to adequately approximate trimester-specific reference intervals. Future efforts should be turned toward studying the meaningfulness of trimester-specific reference intervals and risk-based decision limits.

Hyperthyroidism: aetiology, pathogenesis, diagnosis, management, complications, and prognosis.

Hyperthyroidism is a common condition with a global prevalence of 0·2-1·3%. When clinical suspicion of hyperthyroidism arises, it should be confirmed by biochemical tests (eg, low TSH, high free thyroxine [FT4], or high free tri-iodothyonine [FT3]). If hyperthyroidism is confirmed by biochemical tests, a nosological diagnosis should be done to find out which disease is causing the hyperthyroidism. Helpful tools are TSH-receptor antibodies, thyroid peroxidase antibodies, thyroid ultrasonography, and scintigraphy. Hyperthyroidism is mostly caused by Graves' hyperthyroidism (70%) or toxic nodular goitre (16%). Hyperthyroidism can also be caused by subacute granulomatous thyroiditis (3%) and drugs (9%) such as amiodarone, tyrosine kinase inhibitors, and immune checkpoint inhibitors. Disease-specific recommendations are given. Currently, Graves' hyperthyroidism is preferably treated with antithyroid drugs. However, recurrence of hyperthyroidism after a 12-18 month course of antithyroid drugs occurs in approximately 50% of patients. Being younger than 40 years, having FT4 concentrations that are 40 pmol/L or higher, having TSH-binding inhibitory immunoglobulins that are higher than 6 U/L, and having a goitre size that is equivalent to or larger than WHO grade 2 before the start of treatment with antithyroid drugs increase risk of recurrence. Long-term treatment with antithyroid drugs (ie, 5-10 years of treatment) is feasible and associated with fewer recurrences (15%) than short-term treatment (ie, 12-18 months of treatment). Toxic nodular goitre is mostly treated with radioiodine (131I) or thyroidectomy and is rarely treated with radiofrequency ablation. Destructive thyrotoxicosis is usually mild and transient, requiring steroids only in severe cases. Specific attention is given to patients with hyperthyroidism who are pregnant, have COVID-19, or have other complications (eg, atrial fibrillation, thyrotoxic periodic paralysis, and thyroid storm). Hyperthyroidism is associated with increased mortality. Prognosis might be improved by rapid and sustained control of hyperthyroidism. Innovative new treatments are expected for Graves' disease, by targeting B cells or TSH receptors.

Thyroid autoimmunity and pregnancy in euthyroid women.

Women with thyroid autoimmunity (TAI), predominately characterized by increased levels of thyroid peroxidase antibody (TPOAb), are at risk for developing pregnancy related complications. In this review, we discuss the importance of TAI during natal and perinatal stages. Before pregnancy, TAI is associated with higher mean serum TSH levels and certain causes of subfertility. During pregnancy, TAI increases the risk of an insufficient response of the thyroid to an increasing strain induced by pregnancy, and consequently (subclinical) hypothyroidism might develop. Euthyroid women with TAI have a higher rate of maternal and foetal complications, but it seems that causality cannot be pinned down to thyroid dysfunction alone. Almost half of the women known with TAI prior to pregnancy will also develop post-partum thyroiditis (PPT). However, any relation between PPT and post-partum depression remains uncertain. More research is required to explain possible associations between TAI and pregnancy morbidities, and studies should focus on a better understanding of TAI as such. Given the many unanswered questions, at present, it is not recommended to screen all (potentially) pregnant women for the presence of TAI.

An Exceptional Cause of Increased 18F-Fluorodeoxyglucose Uptake on PET/CT in a Thyroid Nodule.

A 41-year-old female underwent a cervical spine CT for the workup of posterior neck pain irradiating to the shoulders for several months. An incidental thyroid nodule was found and classified as Bethesda III on the Fine-needle aspiration cytology (FNAC) results. Three months later, the patient developed mild shortness of breath, dry cough, and fever. Chest X-ray revealed a mild enlargement in the bilateral hilar regions. CT showed mediastinal and bilateral hilar enlarged lymph nodes and pulmonary micronodules. The workup was further completed with a 18F-FDG PET/CT, showing intense FDG uptake in the mediastinal and bilateral hilar lymph nodes and increased uptake in the thyroid nodule. Endobronchial Ultrasound-guided Transbronchial needle aspiration (EBUS-TBNA) of a left hilar lymph node showed epithelioid non-necrotizing granulomas. Because of the FNAC results, size of the nodule and tracheal shift, thyroid lobectomy was performed one month later. Histopathological results also revealed multiple non-necrotizing epithelioid granulomas, suggesting systemic sarcoidosis with involvement of the thyroid. To our knowledge, this is the first report of thyroid sarcoidosis detected on 18F-FDG PET/CT. Although an increased FDG uptake in a thyroid nodule is usually suggestive of thyroid malignancy, toxic nodule, or follicular hyperplasia, our case report shows that it could also suggest thyroid sarcoidosis.

Impact of thyroid hormone treatment on maternal pregnancy outcomes in women with subclinical hypothyroidism without TPOAb: a retrospective cross-sectional study.

BACKGROUND: Evidence on the impact of thyroid hormone treatment (LT4) on maternal pregnancy outcomes in women with subclinical hypothyroidism (SCH) without thyroid peroxidase antibodies (TPOAb) positivity is scarce. METHODS: Single centre, cross-sectional study in 1460 women screened for TSH, free T4 and TPOAb at median 13 (11-17) weeks of gestation during the period 2013-2014. Exclusion criteria were twin- and assisted reproduction pregnancies, TPO positivity, overt thyroid dysfunction, and treatment with LT4 before screening. The impact of LT4 on maternal pregnancy outcomes was investigated in a group of 53 women with SCH (TSH > 3.74 mIU/L) in which LT4 was initiated at median 13 (10-22) weeks (treated group). The control group included 18 women with SCH (TSH > 3.74 mIU/L). The prevalence of pregnancy complications in these two groups was compared with that in a euthyroid reference (REF) group of 1389 women (TSH ≤ 3.74 mIU/L). RESULTS: The prevalence of pre-eclampsia and gestational diabetes (GDM) was higher in the control group vs the REF group (16.7% vs 5.0% and 27.8% vs 18.9%; p = 0.017 and p = 0.016, respectively), but comparable in the treated group vs the REF group (7.6% vs 5.0% and 22.6% vs 18.9%; p = 0.918 and 0.676, respectively). The prevalence of iron-deficiency anaemia was lower in the treated vs the REF group (17.0% vs 32.5%; p = 0.017). CONCLUSION: Pregnant women with untreated SCH and without TPOAb positivity had a higher prevalence of pre-eclampsia and GDM compared with euthyroid women, while this was not the case in women with treated SCH, even when it was initiated after the first trimester.

Gestation-suppressed serum TSH levels during early pregnancy are not associated with altered maternal and neonatal outcomes.

Objective: The aim of the study was to investigate the impact of suppressed serum TSH levels (sTSH) during early pregnancy on maternal and neonatal outcomes. Methods: In this single-centre, retrospective cohort study 1081 women were screened at 11.8 ± 2.4 weeks of pregnancy for TSH, free T4 (FT4) and TPOAb. Exclusion criteria were twin- and assisted- reproduction pregnancies, women with TSH levels >3.74 mIU/L, severe hyperthyroidism, treated for thyroid dysfunction before or after screening and gestational blood sampling <6 or >16 weeks of pregnancy. The prevalence of adverse pregnancy outcomes was compared between the study group sTSH (TSH: < 0.06 mIU/L; n = 36) and euthyroid controls (TSH: 0.06-3.74 mIU/L; n = 1045), and the impact of sTSH on pregnancy outcomes verified in logistic regression analyses. Results: Median (IQR) serum TSH level in women with sTSH was 0.03 (0.03-0.03) vs 1.25 (0.81-1.82) mIU/L in controls and FT4 levels 18.0 (14.4-20.3) vs 14.2 (12.9-15.4) pmol/L; both P < 0.001. None of the women with sTSH had thyrotropin receptor antibodies. Compared with controls, the prevalence of TPOAb positivity (TAI) was comparable between groups (5.6% vs 6.6%; P = 0.803). The prevalence of maternal and neonatal pregnancy outcomes was comparable between the study and control group. The logistic regression analyses with corrections for TAI, FT4 and demographic parameters confirmed the absence of an association between sTSH, and the following outcomes: iron deficient anaemia (aORs (95% CI)): 1.41 (0.64-2.99); P = 0.385, gestational diabetes: 1.19 (0.44-2.88); P = 0.713, preterm birth: 1.57 (0.23-6.22);P = 0.574 and low Apgar-1' score: 0.71 (0.11-2.67); P = 0.657. Conclusions: Suppressed serum TSH levels during the first to early second trimester of pregnancy were not associated with altered maternal or neonatal outcomes.

New-onset Graves' disease following SARS-CoV-2 vaccination: a case report.

A 22-year-old male with a history of ulcerative colitis and nephrotic syndrome treated with immunomodulatory agents including vedolizumab and mycophenolic acid developed hyperthyroidism 2 weeks following the first administration of BNT162b2 vaccine (Pfizer-BioNTech COVID-19 vaccine). Graves' disease (GD) was diagnosed based on the elevated thyrotropin-receptor antibody, thyroid scintigraphy and ultrasound. To this day, four cases of new-onset GD following SARS-CoV-2 vaccine were reported in patients with no previous history of thyroid disease. Two cases of recurrence of GD following SARS-CoV-2 vaccine were also reported. Although the underlying mechanisms of vaccine-induced autoimmunity remain to be clarified, there is a rationale for the association between SARS-CoV-2 vaccination and the development of Th1-mediated diseases, at least in predisposed individuals. The BNT162b2 vaccine could be a trigger for GD in some patients. However, the benefit/risk ratio remains by far in favour of SARS-CoV-2 vaccination considering the potentially higher risk of severe infection in these patients.

Does foetal gender influence maternal thyroid parameters in pregnancy?

Objective: It is unknown if foetal gender influences maternal thyroid function during pregnancy. We therefore investigated the prevalence of thyroid disorders and determined first-trimester TSH reference ranges according to gender. Methods: A cross-sectional study involving 1663 women with an ongoing pregnancy was conducted. Twin and assisted pregnancies and l-thyroxine or antithyroid treatment before pregnancy were exclusion criteria. Serum TSH, free T4 (FT4) and thyroid peroxidase antibodies (TPOAb) were measured at median (interquartile range; IQR) 13 (11-17) weeks of gestation. Subclinical hypothyroidism (SCH) was present when serum TSH levels were >3.74 mIU/L with normal FT4 levels (10.29-18.02 pmol/L), and thyroid autoimmunity (TAI) was present when TPOAb were ≥60 kIU/L. Results: Eight hundred and forty-seven women were pregnant with a female foetus (FF) and 816 with a male foetus (MF). In women without TAI and during the gestational age period between 9 and 13 weeks (with presumed high-serum hCG levels), median (IQR range) serum TSH in the FF group was lower than that in the MF group: 1.13 (0.72-1.74) vs 1.24 (0.71-1.98) mIU/L; P = 0.021. First-trimester gender-specific TSH reference range was 0.03-3.53 mIU/L in the FF group and 0.03-3.89 mIU/L in the MF group. The prevalence of SCH and TAI was comparable between the FF and MF group: 4.4% vs 5.4%; P = 0.345 and 4.9% vs 7.5%; P = 0.079, respectively. Conclusions: Women pregnant with an MF have slightly but significantly higher TSH levels and a higher upper limit of the first-trimester TSH reference range, compared with pregnancies with a FF. We hypothesise that this difference may be related to higher hCG levels in women pregnant with a FF, although we were unable to measure hCG in this study. Further studies are required to investigate if this difference has any clinical relevance.

Association between thyroid autoimmunity and gestational diabetes mellitus in euthyroid women.

Objective: Pregnant women with autoimmune (subclinical) hypothyroidism have an increased risk of developing gestational diabetes mellitus (GDM). However, this association remains controversial in euthyroid women with thyroid autoimmunity (TAI). Therefore, the aim of the study was to determine the association between TAI and GDM in euthyroid women in a logistic regression analysis with adjustments for baseline/demographic parameters. Methods: Cross-sectional study in 1447 euthyroid women who performed their entire clinical/biological workup and oral glucose tolerance test (OGTT) in our center. At median 13 (11-17) weeks of gestation, thyroid-stimulating hormone, free T4, and thyroid peroxidase antibodies (TPOAb) were measured, baseline characteristics were recorded, and an OGTT was performed between 24 and 28 weeks of pregnancy. Exclusion criteria were pre-pregnancy diabetes, assisted pregnancies, and women with (treated) thyroid dysfunction before or after screening. The diagnosis of GDM was based on 2013 World Health Organization criteria, and TAI was defined as TPOAb levels ≥60 kIU/L. Results: Two hundred eighty women were diagnosed with GDM (19.4%), 26.1% in women with TAI, and 18.9% in women without TAI (P = 0.096). In the logistic regression analysis, TAI was associated with GDM in women older than 30 years (adjusted odds ratio 1.68 (95% CI, 1.01-2.78); P = 0.048). Maternal age >30 years, pre-pregnancy BMI ≥30 kg/m2, and other than Caucasian background were also associated with GDM; aOR 1.93 (95% CI, 1.46-2.56); P < 0.001, 2.03 (95% CI, 1.46-2.81); P < 0.001 and 1.46 (95% CI, 1.03-2.06); P = 0.034, respectively. Conclusions: In older pregnant women, the presence of TAI in euthyroid women was associated with GDM. In line with the literature data, (higher) age and BMI were strongly associated with GDM. Future investigations should focus on treatments that might prevent the development of GDM in euthyroid women with TAI.