Risk Factors for Thyroid Dysfunction in Pregnancy: An Individual Participant Data Meta-Analysis.

Background: International guidelines recommend targeted screening to identify gestational thyroid dysfunction. However, currently used risk factors have questionable discriminative ability. We quantified the risk for thyroid function test abnormalities for a subset of risk factors currently used in international guidelines. Methods: We included prospective cohort studies with data on gestational maternal thyroid function and potential risk factors (maternal age, body mass index [BMI], parity, smoking status, pregnancy through in vitro fertilization, twin pregnancy, gestational age, maternal education, and thyroid peroxidase antibody [TPOAb] or thyroglobulin antibody [TgAb] positivity). Exclusion criteria were pre-existing thyroid disease and use of thyroid interfering medication. We analyzed individual participant data using mixed-effects regression models. Primary outcomes were overt and subclinical hypothyroidism and a treatment indication (defined as overt hypothyroidism, subclinical hypothyroidism with thyrotropin >10 mU/L, or subclinical hypothyroidism with TPOAb positivity). Results: The study population comprised 65,559 participants in 25 cohorts. The screening rate in cohorts using risk factors currently recommended (age >30 years, parity ≥2, BMI ≥40) was 58%, with a detection rate for overt and subclinical hypothyroidism of 59%. The absolute risk for overt or subclinical hypothyroidism varied <2% over the full range of age and BMI and for any parity. Receiver operating characteristic curves, fitted using maternal age, BMI, smoking status, parity, and gestational age at blood sampling as explanatory variables, yielded areas under the curve ranging from 0.58 to 0.63 for the primary outcomes. TPOAbs/TgAbs positivity was associated with overt hypothyroidism (approximate risk for antibody negativity 0.1%, isolated TgAb positivity 2.4%, isolated TPOAb positivity 3.8%, combined antibody positivity 7.0%; p < 0.001), subclinical hypothyroidism (risk for antibody negativity 2.2%, isolated TgAb positivity 8.1%, isolated TPOAb positivity 14.2%, combined antibody positivity 20.0%; p < 0.001) and a treatment indication (risk for antibody negativity 0.2%, isolated TgAb positivity 2.2%, isolated TPOAb positivity 3.0%, and combined antibody positivity 5.1%; p < 0.001). Twin pregnancy was associated with a higher risk of overt hyperthyroidism (5.6% vs. 0.7%; p < 0.001). Conclusions: The risk factors assessed in this study had poor predictive ability for detecting thyroid function test abnormalities, questioning their clinical usability for targeted screening. As expected, TPOAb positivity (used as a benchmark) was a relevant risk factor for (subclinical) hypothyroidism. These results provide insights into different risk factors for gestational thyroid dysfunction.

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.

Association of Gestational Free and Total Triiodothyronine With Gestational Hypertension, Preeclampsia, Preterm Birth, and Birth Weight: An Individual Participant Data Meta-analysis.

CONTEXT: Triiodothyronine (T3) is the bioactive form of thyroid hormone. In contrast to thyroid-stimulating hormone and free thyroxine, we lack knowledge on the association of gestational T3 with adverse obstetric outcomes. OBJECTIVE: To investigate the associaiton of gestational free or total T3 (FT3 or TT3) with adverse obstetric outcomes. METHODS: We collected individual participant data from prospective cohort studies on gestational FT3 or TT3, adverse obstetric outcomes (preeclampsia, gestational hypertension, preterm birth and very preterm birth, small for gestational age [SGA], and large for gestational age [LGA]), and potential confounders. We used mixed-effects regression models adjusting for potential confounders. RESULTS: The final study population comprised 33 118 mother-child pairs of which 27 331 had data on FT3 and 16 164 on TT3. There was a U-shaped association of FT3 with preeclampsia (P = .0069) and a J-shaped association with the risk of gestational hypertension (P = .029). Higher TT3 was associated with a higher risk of gestational hypertension (OR per SD of TT3 1.20, 95% CI 1.08 to 1.33; P = .0007). A lower TT3 but not FT3 was associated with a higher risk of very preterm birth (OR 0.72, 95% CI 0.55 to 0.94; P = .018). TT3 but not FT3 was positively associated with birth weight (mean difference per 1 SD increase in TT3 12.8, 95% CI 6.5 to 19.1 g, P < .0001) but there was no association with SGA or LGA. CONCLUSION: This study provides new insights on the association of gestational FT3 and TT3 with major adverse pregnancy outcomes that form the basis for future studies required to elucidate the effects of thyroid function on pregnancy outcomes. Based on the current study, routine FT3 or TT3 measurements for the assessment of thyroid function during pregnancy do not seem to be of added value in the risk assessment for adverse outcomes.

Association of gestational thyroid function and thyroid peroxidase antibody positivity with postpartum depression: a prospective cohort study and systematic literature review with meta-analysis.

IMPORTANCE: Postpartum depression (PPD) has a major impact on maternal and offspring well-being, with multiple possible risk factors: Studies on the association of thyroid peroxidase antibody (TPOAb) positivity and thyroid function with PPD provide heterogeneous results. OBJECTIVE: To study the association of thyroid function and TPOAb positivity with PPD. DESIGN: We assessed the association of TPOAb and thyroid function with PPD in a population-based prospective cohort study and performed a systematic literature review and meta-analysis. METHODS: We measured thyroid stimulating hormone (TSH), free thyroxine (FT4), and TPOAb between 9- and 17-week gestation. Postpartum depression was assessed with Edinburgh Postpartum Depression Scale at 2-month postpartum and Brief Symptom Inventory at 2-, 6-, and 36-month postpartum. Additionally, we performed a systematic literature review and meta-analysis assessing this association. RESULTS: In the present study, there was no association of thyroid function with PPD (TSH: odds ratio [OR] 0.83, 95% CI 0.58-1.19, P = .32; FT4: OR 0.99, 95% CI 0.95-1.05, P = .86) or TPOAb positivity with PPD (OR 0.79, 95% CI 0.47-1.33, P = .37). An impaired thyroidal response to human chorionic gonadotropin (hCG), a surrogate marker for TPOAb positivity, was associated with a lower risk of PPD (P for interaction TSH = 0.04; FT4 = 0.06). Our systematic review and meta-analysis included 3 articles that were combined with the present study. There was no statistically significant association of TPOAb positivity with PPD (OR 1.93, 95% CI 0.91-4.10, P = .08), but the results were heterogeneous (I2 = 79%). CONCLUSIONS AND RELEVANCE: There was no significant association of TPOAb positivity, TSH, or FT4 with PPD. Our systematic review and meta-analysis revealed high heterogeneity of the current literature. Although TPOAb-positive women should be monitored for postpartum thyroiditis, our findings do not support routinely screening for PPD.

TSH and FT4 Reference Intervals in Pregnancy: A Systematic Review and Individual Participant Data Meta-Analysis.

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.

Metastasis Risk of Cutaneous Squamous Cell Carcinoma in Organ Transplant Recipients and Immunocompetent Patients.

Organ transplant recipients (OTRs) have a high incidence of cutaneous squamous cell carcinoma (cSCC), and immunosuppression has been reported to be an important risk factor for metastasis. The aim of this study was to identify the metastasis risk over a 10-year period for 593 patients with cSCC, of whom 134 were OTR and 459 were immunocompetent. Metastasis incidence rate was 1,046 (95% confidence interval (95% CI) 524-2,096) per 100,000 person years in OTR and 656 (95% CI; 388-1,107) in immunocompetent patients, yielding an incidence rate ratio of 1.6 (95% CI 0.67-3.81). In OTRs head/neck location, older age at transplantation and older age at diagnosis of first cSCC were associated with metastatic risk, and 7 out of 8 metastasized tumours were smaller than 2 cm. In immunocompetent patients tumour size and tumour depth were associated with metastasis. In conclusion, we were not able to demonstrate an increased incidence rate of metastasis in OTRs compared with immunocompetent patients. However, OTRs and immunocompetent patients differed with regard to risk factors for metastasis.