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Context: Levothyroxine is one of the most prescribed medications in the United States., Objective: This study explores the appropriateness of levothyroxine prescriptions., Methods: A retrospective multicenter study was conducted on adult patients who were prescribed levothyroxine for the first time between 2017 and 2020 at three academic centers in the United States. We classified each case of levothyroxine initiation into one of three mutually exclusive categories: appropriate (clinically supported), indeterminate (clinically unclear), or nonevidence based (NEB, not clinically supported)., Results: A total of 977 participants were included. The mean age was 55 years (SD 19), there was female (69%) and White race predominance (84%), and 44% had possible hypothyroid symptoms. Nearly half of the levothyroxine prescriptions were considered NEB (528, 54%), followed by appropriate (307, 31%) and indeterminate (118, 12%). The most common reason for NEB prescription was an index thyrotropin (TSH) value of less than 10 mIU/L without previous TSH or thyroxine values (131/528, 25%), for appropriate prescription, was overt hypothyroidism (163/307, 53%), and for an indeterminate prescription was a nonconfirmed subclinical hypothyroidism with TSH greater than or equal to 10 mIU/L (no confirmatory testing) (51/118, 43%). In multivariable analysis, being female (odds ratio [OR]: 1.3; 95% CI, 1.0-1.7) and prescription by a primary care provider (OR: 1.5; 95% CI, 1.2-2.0) were associated with NEB prescriptions., Conclusion: There is a considerable proportion of NEB levothyroxine prescriptions. These results call for additional research to replicate these findings and to explore the perspective of those prescribing and receiving levothyroxine., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Interpretation of thyroid function tests during pregnancy is limited by the generalizability of reference intervals between cohorts due to inconsistent methodology., Objective: (1) To provide an overview of published reference intervals for thyrotropin (TSH) and free thyroxine (FT4) in pregnancy, (2) to assess the consequences of common methodological between-study differences by combining raw data from different cohorts., Methods: (1) Ovid MEDLINE, EMBASE, and Web of Science were searched until December 12, 2021. Studies were assessed in duplicate. (2) The individual participant data (IPD) meta-analysis was performed in participating cohorts in the Consortium on Thyroid and Pregnancy., Results: (1) Large between-study methodological differences were identified, 11 of 102 included studies were in accordance with current guidelines; (2) 22 cohorts involving 63 198 participants were included in the meta-analysis. Not excluding thyroid peroxidase antibody-positive participants led to a rise in the upper limits of TSH in all cohorts, especially in the first (mean +17.4%; range +1.6 to +30.3%) and second trimester (mean +9.8%; range +0.6 to +32.3%). The use of the 95th percentile led to considerable changes in upper limits, varying from -10.8% to -21.8% for TSH and -1.2% to -13.2% for FT4. All other additional exclusion criteria changed reference interval cut-offs by a maximum of 3.5%. Applying these findings to the 102 studies included in the systematic review, 48 studies could be used in a clinical setting., Conclusion: We provide an overview of clinically relevant reference intervals for TSH and FT4 in pregnancy. The results of the meta-analysis indicate that future studies can adopt a simplified study setup without additional exclusion criteria., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Objectives: Thyroid autoimmunity is common in pregnant women and associated with thyroid dysfunction and adverse obstetric outcomes. Most studies focus on thyroid peroxidase antibodies (TPOAbs) assessed by a negative-positive dichotomy and rarely take into account thyroglobulin antibodies (TgAbs). This study aimed at determining the association of TPOAbs and TgAbs, respectively, and interdependently, with maternal thyroid function. Methods: This was a meta-analysis of individual participant cross-sectional data from 20 cohorts in the Consortium on Thyroid and Pregnancy. Women with multiple pregnancy, pregnancy by assisted reproductive technology, history of thyroid disease, or use of thyroid interfering medication were excluded. Associations of (log2) TPOAbs and TgAbs (with/without mutual adjustment) with cohort-specific z-scores of (log2) thyrotropin (TSH), free triiodothyronine (fT3), total triiodothyronine (TT3), free thyroxine (fT4), total thyroxine (TT4), or triiodothyronine:thyroxine (T3:T4) ratio were evaluated in a linear mixed model. Results: In total, 51,138 women participated (51,094 had TPOAb-data and 27,874 had TgAb-data). Isolated TPOAb positivity was present in 4.1% [95% confidence interval, CI: 3.0 to 5.2], isolated TgAb positivity in 4.8% [CI: 2.9 to 6.6], and positivity for both antibodies in 4.7% [CI: 3.1 to 6.3]. Compared with antibody-negative women, TSH was higher in women with isolated TPOAb positivity (z-score increment 0.40, CI: 0.16 to 0.64) and TgAb positivity (0.21, CI: 0.10 to 0.32), but highest in those positive for both antibodies (0.54, CI: 0.36 to 0.71). There was a dose-response effect of higher TPOAb and TgAb concentrations with higher TSH (TSH z-score increment for TPOAbs 0.12, CI: 0.09 to 0.15, TgAbs 0.08, CI: 0.02 to 0.15). When adjusting analyses for the other antibody, only the association of TPOAbs remained statistically significant. A higher TPOAb concentration was associated with lower fT4 ( p  < 0.001) and higher T3:T4 ratio (0.09, CI: 0.03 to 0.14), however, the association with fT4 was not significant when adjusting for TgAbs ( p  = 0.16). Conclusions: This individual participant data meta-analysis demonstrated an increase in TSH with isolated TPOAb positivity and TgAb positivity, respectively, which was amplified for individuals positive for both antibodies. There was a dose-dependent association of TPOAbs, but not TgAbs, with TSH when adjusting for the other antibody. This supports current practice of using TPOAbs in initial laboratory testing of pregnant women suspected of autoimmune thyroid disease. However, studies on the differences between TPOAb- and TgAb-positive women are needed to fully understand the spectrum of phenotypes.

Background: Subclinical hypothyroidism (SCH) during pregnancy has been associated with multiple adverse maternal and neonatal outcomes. However, the potential benefits of levothyroxine (LT4) supplementation remain controversial. Variations across studies in diagnostic criteria for SCH may, in part, explain the divergent findings on the subject. This study aimed to assess the effect of LT4 treatment on pregnancy and neonatal outcomes among pregnant women who were diagnosed as SCH based on the most recent diagnostic criteria., Methods: We conducted a systematic review and meta-analysis of the literature published from inception to January 2020. The search strategy targeted the studies on pregnancy and neonatal outcomes following LT4 treatment in women with SCH based on 2017 American Thyroid Association diagnostic criteria. Pooled effect sizes were estimated using fixed and random effect models, according to the absence or presence of heterogeneity which was assessed using the I-squared statistic. Sources of heterogeneity and the stability of results were evaluated through sensitivity analysis., Results: Of the 2781 identified references, 306 full-text articles were screened for eligibility. Finally, 6 studies including a total of 7955 participants were retained for analysis. Summary effect estimates indicated that pregnant women with SCH treated with LT4 had a lower risk of pregnancy loss [odds ratio (OR) = 0.55, 95% confidence interval (CI): 0.43-0.71], preterm birth (OR=0.63, 95% CI: 0.41-0.98) and gestational hypertension (OR = 0.78, 95% CI: 0.63-0.97) than those in control group., Conclusion: LT4 treatment in pregnant women with SCH may reduce the risk of pregnancy loss, preterm delivery and gestational hypertension., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ding, Liu, Maraka, Abdelouahab, Huang, Fraser and Fan.)

Background: Combined therapy with levothyroxine (LT4)/L-triiodothyronine (LT3) has garnered attention among clinicians and patients as a potential treatment alternative to LT4 monotherapy. The objective of this study was to compare the benefits and harms of LT4/LT3 combined therapy and LT4 monotherapy for patients with hypothyroidism. Methods: A systematic search in MEDLINE, Scopus, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials was performed by a librarian from inception date until September 2020. Randomized clinical trials and quasiexperimental studies comparing combined therapy (LT4/LT3) versus monotherapy (LT4) for adult patients with hypothyroidism were considered for inclusion. Independent data extraction was performed by paired reviewers. A meta-analysis comparing standardized mean differences of the effect of each therapy was performed on clinical outcomes and patient preferences. Proportions of adverse events and reactions were assessed narratively. Results: A total of 1398 references were retrieved, from which 18 fulfilled the inclusion criteria. Results supported by evidence at low-to-moderate certainty evidence did not display a difference in treatment effect between therapies on clinical status, quality of life, psychological distress, depressive symptoms, and fatigue; all measured with standardized questionnaires. Furthermore, meta-analysis of patient preferences revealed higher proportions of choice for combined therapy (43%) when compared with monotherapy (23%) or having no preference (30%). When evaluating treatment adverse events or adverse reactions, similar proportions were observed between treatment groups; meta-analysis was not possible. Conclusions: The available evidence at low-to-moderate certainty demonstrates that there is no difference in clinical outcomes between LT4/LT3 combined therapy and LT4 monotherapy for treating hypothyroidism in adults, except for a higher proportion of patient preferring combined therapy. Adverse events and reactions appear to be similar across both groups, however, this observation is only narrative. These results could inform shared decision-making conversations between patients with hypothyroidism and their clinicians. PROSPERO Registration ID: CRD42020202658.

Background: Human chorionic gonadotropin (hCG) is a marker of placental function, which also stimulates the maternal thyroid gland. Maternal thyroid function can be associated with the pathophysiology of gestational diabetes mellitus (GDM). We aimed to study whether there is an association of hCG concentrations in early pregnancy with GDM and whether it is mediated through maternal thyroid hormones. Methods: This study included 18,683 pregnant women presenting at a tertiary hospital in Shanghai, China, between January 2015 and December 2016. GDM was diagnosed using a 2-hour, 75-g, oral glucose tolerance test (OGTT) according to the American Diabetes Association guidelines. Multivariable logistic or linear regression models were used to identify associations, adjusting for maternal age, education level, family history of diabetes, parity, fetal sex, thyroperoxidase antibody (TPOAb) status, and prepregnancy body-mass index. Results: Higher hCG concentrations were associated with a lower plasma glucose level during the OGTT, but not with fasting plasma glucose or hemoglobin A1c concentrations tested during early pregnancy. hCG in early pregnancy was negatively associated with GDM risk ( p  = 0.027). Mediation analysis identified that an estimated 21.4% of the association of hCG-associated GDM risk was mediated through changes in free thyroxine (fT4) concentrations ( p  < 0.05). In the sensitivity analysis restricted to TPOAb-positive women, hCG was not associated with GDM ( p  = 0.452). Conclusions: Higher hCG levels in early pregnancy are associated with a lower risk of GDM. Maternal fT4 may act as an important mediator in this association.

Background: Levothyroxine (LT4) is one of the most commonly prescribed medications. Although considered a life-long replacement therapy, LT4 therapy can be discontinued for some patients. This study aims at: (i) reviewing the evidence on clinical outcomes of patients undergoing thyroid hormone replacement discontinuation, (ii) identifying the predictors of successful discontinuation, and (iii) systematically appraising frameworks used for deprescribing thyroid hormone. Methods: We searched multiple bibliographic databases, including Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus, from inception to February 2020 for studies in which thyroid hormone replacement was discontinued. Clinical outcomes assessed included: proportion of patients that remained euthyroid or needed to restart thyroid hormone replacement after discontinuation and frequency of clinical symptoms of hypothyroidism and adverse effects. We also evaluated predictors for discontinuation and deprescribing frameworks. Reviewers (F.J.K.T., N.B., N.M.S.O., S.M.) evaluated studies for inclusion, extracted data, and assessed methodological quality independently and in duplicate. Results: Seventeen observational studies at moderate to high risk of bias met inclusion criteria, including a total of 1103 patients (86% women) with an age range of 2-81 years. Approximately a third of patients undergoing thyroid hormone discontinuation remained euthyroid at follow-up (37.2%, 95% confidence interval [CI 24.2-50.1%], I 2 97.5%). Subgroup analysis showed that patients with a previous diagnosis of overt hypothyroidism (OH) were less likely to remain euthyroid (11.8% [CI 0.4-23.2%], I 2 90.3%) than patients with a prior diagnosis of subclinical hypothyroidism (SCH) (35.6% [CI 8.2-62.9%], I 2 94.0%). No study followed a framework for systematically deprescribing LT4. Conclusions: Low-quality evidence suggests that up to a third of patients remained euthyroid after thyroid hormone discontinuation, with a higher proportion of patients with an initial diagnosis of SCH remaining euthyroid than patients with an initial diagnosis of OH. A deprescribing framework focusing on adequate selection of patients for deprescribing LT4 and a systematic process is warranted to guide clinicians in re-evaluating the need for LT4 in their patients.

Background: The use of prescribed medications during pregnancy is a challenge and an underestimated source of treatment burden. Levothyroxine (LT4) for the treatment of overt and subclinical hypothyroidism is extensively prescribed during pregnancy. To this end, we aimed to explore the patients' perceived benefits and risks, knowledge, beliefs, attitudes, and related burden of LT4 therapy during pregnancy. Methods: In this cross-sectional study, we surveyed pregnant women who were treated with LT4 during pregnancy from January 1, 2019, to December 31, 2019, in a tertiary academic medical center of the United States. The anonymous online survey included questions to gather demographic data and multiple-choice questions regarding the benefits and risks, knowledge, beliefs, attitudes, and burden related to LT4 use during pregnancy. Results: Sixty-four pregnant women (mean age 31.5 years) completed the study survey (response rate: 96%): 62% were diagnosed with hypothyroidism more than 12 months before pregnancy, 16% less than or about 12 months before pregnancy, and 22% during pregnancy. We found that one-third of pregnant women using LT4 had a feeling of uneasiness/anxiety due to their hypothyroidism diagnosis. About half of the respondents (45%) reported that they did not receive an explanation by their clinician regarding the maternal/fetal risks of uncontrolled hypothyroidism or the benefits of adequate control. Finally, two in three patients expressed various concerns of LT4-related treatment burden. Conclusions: Our findings support the need for increased effective communication and tailored counseling to address fears, anxiety, and uncertainties about the benefits and risks of LT4 use in pregnancy. For patients with clear benefits from LT4 treatment in pregnancy, it could help to overcome their concerns, promote adherence, and decrease adverse maternal/fetal outcomes. For patients with no clear benefits established, clinicians need to be aware of LT4-related treatment burden in pregnancy and implement patient-centered approaches in their clinical practices.

Objective: Uncontrolled hypothyroidism has been associated with an increased risk of adverse pregnancy outcomes. We aimed to assess the effectiveness of increasing levothyroxine (LT4) dose on reducing the risk of adverse outcomes for pregnant women with TSH level greater than the recommended 1st trimester limit., Design, Patients, Measurements: We reviewed the electronic medical records of pregnant women evaluated from January 2011 to December 2013, who had history of LT4-treated hypothyroidism and were found to have TSH > 2·5 mIU/l in 1st trimester. Women were divided into two groups: group A - LT4 dose was increased within two weeks from the TSH test, group B - LT4 dose remained stable. We compared the frequency of pregnancy loss (primary outcome) and other prespecified pregnancy-related adverse outcomes between groups., Results: There were 85 women in group A (median TSH: 5·0, interquartile range 3·8-6·8 mIU/l) and 11 women in group B (median TSH: 4·5, interquartile range 3·2-4·9 mIU/l). The groups were not different in baseline clinical and socioeconomic characteristics. The mean interval between TSH test and LT4 dose increase was 4·5 (SD 4·6) days. Pregnancy loss was significantly lower in group A (2/85, 2·4%) vs group B (4/11, 36·4%) (P = 0·001). Other pregnancy-related adverse outcomes were similar between groups., Conclusions: Increasing LT4 dose for women with uncontrolled hypothyroidism in the 1st trimester of pregnancy was associated with a decreased risk of pregnancy loss. Given the limitations of our study, this association awaits further confirmation from larger studies., (© 2016 John Wiley & Sons Ltd.)

Background: Subclinical hypothyroidism (SCH) has been associated with increased risk of adverse pregnancy outcomes in some, but not all, studies. Uncertainty remains regarding the impact of levothyroxine (LT4) therapy on improving health outcomes in pregnant women with SCH. The objective of this study was to assess the potential benefits of LT4 therapy in pregnant women with SCH., Methods: The medical records were reviewed of pregnant women with SCH, defined as an elevated serum thyrotropin (TSH) of >2.5 mIU/L for the 1st trimester or >3 mIU/L for the 2nd and 3rd trimesters, but ≤10 mIU/L. Pregnant women were divided into two groups depending on whether they received LT4 (group A) or not (group B). Pregnancy loss and other pre-specified adverse outcomes were evaluated during follow-up., Results: There were 82 women in group A and 284 in group B. Group A had a higher body mass index (p = 0.04) and a higher serum TSH level (p < 0.0001) compared with group B. Group A had fewer pregnancies lost (n = 5 [6.1%] vs. n = 25 [8.8%]; p = 0.12), low birth weight (LBW) offspring (1.3% vs. 10%; p < 0.001), and no neonates with a five-minute Apgar score ≤7 (0% vs. 7%; p < 0.001) compared with group B. Other pregnancy-related adverse outcomes were similar between the two groups. Inferences remained unchanged after considering different models to adjust for potential predictors of outcome., Conclusions: LT4 therapy is associated with a decreased risk of LBW and a low Apgar score among women with SCH. This association awaits confirmation in randomized trials before the widespread use of LT4 therapy in pregnant women with SCH.

Background: The impact of subclinical hypothyroidism (SCH) and of levothyroxine replacement in pregnant women with SCH is unclear. The aims of this study were to assess (i) the impact of SCH during pregnancy on maternal and neonatal outcomes, and (ii) the effect of levothyroxine replacement therapy in these patients., Methods: Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid MEDLINE, the Cochrane Controlled Trials Register, Ovid EMBASE, Web of Science, and Scopus were searched from inception to January 2015. Randomized trials and cohort studies of pregnant women with SCH that examined adverse pregnancy and neonatal outcomes were included. Reviewers extracted data and assessed methodological quality in duplicate. Eighteen cohort studies at low-to-moderate risk of bias were included. Compared with euthyroid pregnant women, pregnant women with SCH were at higher risk for pregnancy loss (relative risk [RR] 2.01 [confidence interval (CI) 1.66-2.44]), placental abruption (RR 2.14 [CI 1.23-3.70]), premature rupture of membranes (RR 1.43 [CI 1.04-1.95]), and neonatal death (RR 2.58 [CI 1.41-4.73]). One study at high risk of bias compared pregnant women with SCH who received levothyroxine to those who did not and found no significant decrease in the rate of pregnancy loss, preterm delivery, gestational hypertension, low birth weight, or low Apgar score., Conclusions: SCH during pregnancy is associated with multiple adverse maternal and neonatal outcomes. The value of levothyroxine therapy in preventing these adverse outcomes remains uncertain.