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1.
Artigo em Inglês | MEDLINE | ID: mdl-38650165

RESUMO

INTRODUCTION: A considerable amount of neonatal morbidity and mortality worldwide is caused by preterm birth. To date, the underlying etiology of preterm birth has not been fully clarified. Previous studies demonstrate that inflammation is one of the pathological factors that might cause preterm birth, and that there is a difference between primiparous and multiparous women in immune response to pregnancy. The objective of this prospective cohort study was to investigate the role of two inflammatory markers, ferritin and C-reactive protein (CRP) and preterm birth, in first trimester women, stratified for parity. In addition, a possible association between high ferritin and CRP, and a possible association between high ferritin and CRP and preterm birth were assessed. MATERIAL AND METHODS: A total of 2044 healthy, low-risk pregnant women from primary obstetric care in the Netherlands participated in this study. Their ferritin and CRP levels were evaluated at 12 weeks' gestation. Levels above the parity specific 95th percentile were defined as high. The main outcome of this study was to assess the presence of a possible association between parity specific high ferritin and CRP, and preterm birth. The secondary outcomes were the ferritin and CRP levels of women, stratified for parity, and the possible association between high ferritin and CRP levels. Logistic regression analysis was performed with preterm birth as a dependent variable and parity specific high ferritin and CRP as an independent variable, adjusting for age and history of preterm birth. RESULTS: Ferritin levels decreased with increasing parity. Ferritin and CRP levels at 12 weeks' gestation were significantly higher in women with preterm birth. In primiparous women, high ferritin levels (OR: 2.5, CI: 1.14-5.38) and high CRP levels (OR: 5.0, CI: 2.61-9.94) were independently associated with preterm birth. In multiparous women, high ferritin levels (OR: 6.0, CI: 2.28-16.67) were independently associated with preterm birth while high CRP levels were not. CONCLUSIONS: First trimester parity specific ferritin and CRP levels could play a part in predictive models for preterm birth, and further research for their additive role in preterm birth is needed.

2.
Thyroid ; 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38546971

RESUMO

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.

3.
Environ Pollut ; 346: 123513, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38350534

RESUMO

Per- and polyfluoroalkyl substances (PFAS) exposure was associated with changes in thyroid function in pregnant mothers and the general population. Limited such evidence exists in other susceptible populations such as females with fertility problems. This cross-sectional study included 287 females seeking medically assisted reproduction at a fertility clinic in Massachusetts, United States, between 2005 and 2019. Six long-alkyl chain PFAS, thyroid hormones, and autoimmune antibodies were quantified in baseline serum samples. We used generalized linear models and quantile g-computation to evaluate associations of individual PFAS and their total mixture with thyroid biomarkers. Most females were White individuals (82.7%), had graduate degrees (57.8%), and nearly half had unexplained subfertility (45.9%). Serum concentrations of all examined PFAS and their mixture were significantly associated with 2.6%-5.6% lower total triiodothyronine (TT3) concentrations. Serum concentrations of perfluorononanoate (PFNA), perfluorodecanoate (PFDA), and perfluoroundecanoate (PFUnDA), and of the total mixture were associated with higher ratios of free thyroxine (FT4) to free triiodothyronine (FT3). No associations were found for PFAS and TSH or autoimmune antibodies. Our findings support the thyroid-disrupting effect of long alkyl-chain PFAS among a vulnerable population of subfertile females.


Assuntos
Ácidos Alcanossulfônicos , Poluentes Ambientais , Fluorocarbonos , Gravidez , Humanos , Feminino , Glândula Tireoide , Tri-Iodotironina , Estudos Transversais , Clínicas de Fertilização , Hormônios Tireóideos , Biomarcadores
4.
Lung Cancer ; 189: 107477, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38271919

RESUMO

OBJECTIVES: Timely diagnosis of lung cancer (LC) is crucial to achieve optimal patient care and outcome. Moreover, the number of procedures required to obtain a definitive diagnosis can have a large influence on the life expectancy of a patient. Here, adherence with existing Dutch guidelines for timeliness and type and number of invasive and imaging procedures was assessed. MATERIALS AND METHODS: 1096 patients with suspected LC were enrolled in this multicenter prospective study (NL9146). The overall survival, time from referral to the first appointment with the pulmonologist, time to diagnosis and treatment, and the number of imaging and invasive procedures were evaluated. Patients were divided into different diagnostic groupsearly- and advanced stage non-small-cell lung cancer (NSCLC), small-cell lung cancer (SCLC), large cell neuroendocrine carcinoma of the lung (LCNEC), patients without LC and patients without a definitive diagnosis. RESULTS: The majority of patients (66 %) received a definitive diagnosis within 5 weeks, although the time to diagnosis of early-stage LC patients and patients without LC was significantly longer comparted to advanced stage LC. An increase in invasive procedures was seen for early-stage LC compared to advanced stage LC and for 13 % of the advanced stage non-squamous NSCLC patients up to three additional invasive procedures were performed solely to obtain sufficient material for NGS. For patients without a definitive diagnosis, 50 % did undergo at least one invasive procedure, while 11 % did not wish to undergo any invasive procedures. CONCLUSION: These insights could aid in improved LC diagnostics and efficient implementation of new techniques like liquid biopsy and artificial intelligence. This may lead to more timely LC care, a decreased number of invasive procedures, less variability between the diagnostic trajectory of different patients and aid in obtaining a definitive diagnosis for all patients.


Assuntos
Carcinoma Neuroendócrino , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/terapia , Inteligência Artificial , Estudos Prospectivos , Hospitais , Pulmão
5.
Clin Chem Lab Med ; 62(4): 720-728, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-37886827

RESUMO

OBJECTIVES: Numerous studies have proven the potential of cytokeratin 19 fragment 21-1 (CYFRA 21-1) detection in the (early) diagnosis and treatment monitoring of non-small cell lung cancer (NSCLC). Conventional immunoassays for CYFRA 21-1 quantification are however prone to interferences and lack diagnostic sensitivity and standardization. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is an emerging approach based on a different, often superior, detection principle, which may improve the clinical applicability of CYFRA 21-1 in cancer diagnostics. Therefore, we developed and validated a protein precipitation, immunoaffinity (IA) LC-MS/MS assay for quantitative analysis of serum CYFRA 21-1. METHODS: Selective sample preparation was performed using ammonium sulfate (AS) precipitation, IA purification, tryptic digestion and LC-MS/MS quantification using a signature peptide and isotopically labeled internal standard. The workflow was optimized and validated according to EMA guidelines and results were compared to a conventional immunoassay. RESULTS: Significant interference effects were seen during IA purification, which were sufficiently solved by performing AS precipitation prior to IA purification. A linear calibration curve was obtained in the range of 1.0-100 ng/mL (R2=0.98). Accuracy and precision were well within acceptance criteria. In sera of patients suspected of lung cancer, the method showed good correlation with the immunoassay. CONCLUSIONS: A robust AS precipitation-IA LC-MS/MS assay for the quantification of serum CYFRA 21-1 was developed. With this assay, the clinically added value of LC-MS/MS-based detection over immunoassays can be further explored.


Assuntos
Antígenos de Neoplasias , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Cromatografia Líquida/métodos , Queratina-19 , Espectrometria de Massas em Tandem/métodos , Neoplasias Pulmonares/diagnóstico , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/diagnóstico
6.
J Clin Endocrinol Metab ; 109(3): 868-878, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-37740543

RESUMO

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.


Assuntos
Hipotireoidismo , Testes de Função Tireóidea , Gravidez , Humanos , Feminino , Prevalência , Hipotireoidismo/diagnóstico , Hipotireoidismo/epidemiologia , Tiroxina , Tireotropina , Valores de Referência
7.
Sens Diagn ; 2(6): 1492-1500, 2023 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-38013761

RESUMO

Therapeutic drug monitoring (TDM) of tumor necrosis factor-α (TNFα)-inhibitors adalimumab and infliximab is important to establish optimal drug dose and maximize treatment efficacy. Currently, TDM is primarily performed with ELISA techniques in clinical laboratories, resulting in a long sample-to-result workflow. Point-of-care (POC) detection of these therapeutic antibodies could significantly decrease turnaround times and allow for user-friendly home-testing. Here, we adapted the recently developed bioluminescent dRAPPID (dimeric Ratiometric Plug-and-Play Immunodiagnostics) sensor platform to allow POC TDM of infliximab and adalimumab. We applied the two best performing dRAPPID sensors, with limit-of-detections of 1 pM and 17 pM, to measure the infliximab and adalimumab levels in 49 and 40 patient serum samples, respectively. The analytical performance of dRAPPID was benchmarked with commercial ELISAs and yielded Pearson's correlation coefficients of 0.93 and 0.94 for infliximab and adalimumab, respectively. Furthermore, a dedicated bioluminescence reader was fabricated and used as a readout device for the TDM dRAPPID sensors. Subsequently, infliximab and adalimumab patient serum samples were measured with the TDM dRAPPID sensors and bioluminescence reader, yielding Pearson's correlation coefficients of 0.97 and 0.86 for infliximab and adalimumab, respectively, and small proportional differences with ELISA (slope was 0.97 ± 0.09 and 0.96 ± 0.20, respectively). The adalimumab and infliximab dRAPPID sensors, in combination with the dedicated bioluminescence reader, allow for ease-of-use TDM with a fast turnaround time and show potential for POC TDM outside of clinical laboratories.

8.
Environ Int ; 178: 108091, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37459690

RESUMO

BACKGROUND: Human chorionic gonadotropin (hCG) is produced by the placenta and plays an essential role in the maintenance of pregnancy. Endocrine disrupting chemicals (EDCs) have the potential to interfere with functions related to the production and secretion of hCG; however associations between exposure to EDCs and hCG concentrations in humans remain to be elucidated. OBJECTIVES: To investigate the association of urinary, serum and plasma concentrations of EDCs during pregnancy with serum hCG concentrations. METHODS: We utilized data form the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy (SELMA) study. We investigated the association of 26 EDCs measured in early pregnancy urine or blood with serum hCG concentrations using multi-variable adjusted linear regression models per EDC and Weighted Quantile Sum (WQS) regression with repeated holdout validation for the EDCs mixture. RESULTS: In 2,039 included women, higher exposure to bisphenol A was associated with lower hCG (beta [95% CI]: -0.06 [-0.11 to -0.002]) while higher triclosan exposure was associated with a higher hCG (0.02 [0.003 to 0.04]). Higher exposure to several phthalates, including mono-ethyl and mono-butyl phthalates (MEP and MBP) as well as metabolites of di-2-ethylhexyl phthalate (DEHP) was associated with a lower hCG (beta [95% CI] for sum of DEHP metabolites: -0.13 [-0.19 to -0.07]). Likewise, higher exposure to several polychlorinated biphenyls (PCBs) was associated with a lower hCG. In the WQS regression, each quartile increase in the EDCs mixture was associated with -0.27 lower hCG (95% CI: -0.34 to -0.19). DISCUSSION: Higher exposure to several EDCs during pregnancy was associated with a lower hCG; and despite the small effect sizes, still indicating that the exposure may negatively affect production or secretion of hCG by the placenta. Our results provide the impetus for future experimental studies to investigate the placenta as a target organ for adverse effects of EDCs.


Assuntos
Dietilexilftalato , Disruptores Endócrinos , Poluentes Ambientais , Ácidos Ftálicos , Bifenilos Policlorados , Gravidez , Criança , Humanos , Feminino , Disruptores Endócrinos/toxicidade , Estudos Longitudinais , Gonadotropina Coriônica , Exposição Ambiental/efeitos adversos
9.
Artigo em Inglês | MEDLINE | ID: mdl-37086508

RESUMO

Neuron-specific enolase (NSE) is a promising small-cell lung cancer (SCLC) biomarker composed of αγ and γγ isozyme dimers. As the conventional immunoassays are prone to interferences and cannot differentiate between the isozymes, we developed a multiplex immunoaffinity (IA) liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for the quantification of NSEα and NSEγ in human serum. A calibrator was prepared by performing cold denaturation of recombinantly expressed αα and γγ enolase dimers to induce a new dimer equilibrium that was determined to be approximately 1αγ:1γγ:1αα. Selective sample purification was achieved by performing IA extraction using an antibody specific towards NSEγ. The isolated αγ and γγ dimers were denatured and trypsin digested to allow quantification of the selected signature peptides and their corresponding isotopically labelled peptide internal standard. The obtained linear dynamic ranges were determined to be 1.5-56 ng/mL and 0.64-167 ng/mL for NSEα and NSEγ (R2 = 0.88 and 0.97 respectively). Validation of the assay showed acceptable accuracy and precision for NSEα and NSEγ. The method was successfully applied to patient serum in which both isozymes were detected. Compared to the conventional immunoassay, substantially lower total NSE concentrations were measured in IA LC-MS/MS. With this multiplex IA LC-MS/MS assay, the clinical value of quantifying the individual isozymes can be explored. In addition, together with the calibrator described here, it may be applied to standardize NSE immunoassays across different platforms.


Assuntos
Isoenzimas , Espectrometria de Massas em Tandem , Humanos , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Peptídeos , Fosfopiruvato Hidratase , Reprodutibilidade dos Testes
10.
Nutrition ; 109: 111938, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36736090

RESUMO

OBJECTIVES: High plasma copper (Cu) and low zinc (Zn) levels have been associated with depression. However, most studies used low sample sizes and a cross-sectional design, and perinatal data are scarce. We investigated the possible association between pregnancy-specific psychological distress and the plasma CuZn ratio using a prospective design. METHODS: Pregnancy-specific distress symptoms were assessed at each trimester by means of the Tilburg Pregnancy Distress Scale, negative affect subscale, in 2036 pregnant women. Cu and Zn were assessed at 12 wk of gestation in plasma samples by inductively coupled plasma mass spectrometry. Growth mixture modeling determined trajectories of women's pregnancy-specific negative affect (P-NA) symptoms, which were entered in a multiple logistic regression analysis as dependent variable and the CuZn ratio as independent variable. RESULTS: Two P-NA symptom classes were found: 1) persistently low (n = 1820) and 2) persistently high (n = 216). A higher CuZn ratio was independently associated with persistently high P-NA symptom scores (odds ratio = 1.52; 95% confidence interval, 1.13-2.04) after adjustment for confounders. A sensitivity analysis was performed excluding all women with high P-NA scores at 12 wk of gestation (>1 SD above the mean P-NA score). In the 1719 remaining women, a higher CuZn ratio significantly predicted the development of increasing P-NA symptom scores after adjustment for confounders (odds ratio = 1.40; 95% confidence interval, 1.04-1.95). CONCLUSIONS: A higher CuZn plasma ratio is an independent determinant of developing pregnancy-specific distress symptoms throughout pregnancy, suggesting that micronutrients could be used as novel biomarkers for psychological distress research of perinatal mood disorders.


Assuntos
Cobre , Gestantes , Gravidez , Feminino , Humanos , Primeiro Trimestre da Gravidez , Estudos Transversais , Zinco
11.
Lung Cancer ; 178: 28-36, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36773458

RESUMO

OBJECTIVES: Pathologic subtyping of tissue biopsies is the gold standard for the diagnosis of lung cancer (LC), which could be complicated in cases of e.g. inconclusive tissue biopsies or unreachable tumors. The diagnosis of LC could be supported in a minimally invasive manner using protein tumor markers (TMs) and circulating tumor DNA (ctDNA) measured in liquid biopsies (LBx). This study evaluates the performance of LBx-based decision-support algorithms for the diagnosis of LC and subtyping into small- and non-small-cell lung cancer (SCLC and NSCLC) aiming to directly impact clinical practice. MATERIALS AND METHODS: In this multicenter prospective study (NL9146), eight protein TMs (CA125, CA15.3, CEA, CYFRA 21-1, HE4, NSE, proGRP and SCCA) and ctDNA mutations in EGFR, KRAS and BRAF were analyzed in blood of 1096 patients suspected of LC. The performance of individual and combined TMs to identify LC, NSCLC or SCLC was established by evaluating logistic regression models at pre-specified positive predictive values (PPV) of ≥95% or ≥98%. The most informative protein TMs included in the multi-parametric models were selected by recursive feature elimination. RESULTS: Single TMs could identify LC, NSCLC and SCLC patients with 46%, 25% and 40% sensitivity, respectively, at pre-specified PPVs. Multi-parametric models combining TMs and ctDNA significantly improved sensitivities to 65%, 67% and 50%, respectively. CONCLUSION: In patients suspected of LC, the LBx-based decision-support algorithms allowed identification of about two-thirds of all LC and NSCLC patients and half of SCLC patients. These models therefore show clinical value and may support LC diagnostics, especially in patients for whom pathologic subtyping is impossible or incomplete.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Estudos Prospectivos , Biomarcadores Tumorais , Fosfopiruvato Hidratase , Biópsia Líquida
12.
J Pharm Biomed Anal ; 221: 115027, 2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36099723

RESUMO

Establishing dihydropyrimidine dehydrogenase (DPD) activity is highly important in determining the correct starting dose of fluoropyrimidines such as 5-fluorouracil and capecitabine. The concentration ratio of endogenous uracil with its metabolite dihydrouracil (DHU) is a well-known parameter that is linked to DPD activity. Concentration ratios such as thymine over its DPD-converted metabolite dihydrothymine (DHT) is less described and may serve as an alternative diagnostic biomarker for DPD activity. In this study, we describe the development and validation of an ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) assay for the quantification of uracil, DHU, thymine, and DHT in human plasma. In addition, stability experiments were performed. Uracil and thymine were quantified up to 80.0 ng/mL and DHU and DHT up to 800 ng/mL. Intra- and inter-assay precision were maximum 8.0 % and 7.6 %. respectively. Also, recovery was adequate and significant matrix-effects and carry-over were excluded. Stability experiments showed that uracil concentrations increased with 27-52 % when stored for 1 or 2 h at ambient temperatures compared to cold storage. Thymine, DHU, and DHT concentrations remained stable, thymine after 1 h in plasma excluded, showing the DHT:T ratio might be a more robust marker for DPD activity than DHU:U. In conclusion, we present here a novel assay capable of quantifying uracil, thymine, DHU and DHT in a single analytical run. We provide additional data showing increased stability for DHU, thymine and DHT compared to uracil. This assay may be used as a diagnostic test in future studies, establishing the association of these endogenous biomarker concentrations with DPD activity and safety to treatment with fluoropyrimidines. In addition, future research should also be focused on reducing pre-analytical instability. Standardization in this field is essential to set proper reference values and to allow inter-study comparison on clinical outcomes.


Assuntos
Di-Hidrouracila Desidrogenase (NADP) , Timina , Biomarcadores , Capecitabina , Cromatografia Líquida , Di-Hidrouracila Desidrogenase (NADP)/metabolismo , Fluoruracila , Humanos , Espectrometria de Massas em Tandem , Uracila/análogos & derivados
13.
Thyroid ; 32(10): 1249-1258, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35999708

RESUMO

Background: It is unclear whether levels of hypothyroid symptoms in pregnant women with (sub)clinical thyroid dysfunction differ from euthyroid controls and whether free thyroxine (fT4)/thyrotropin (TSH) changes throughout pregnancy affect hypothyroid symptom levels. The objective was twofold: (1) To compare hypothyroid symptom levels between thyroid dysfunction subgroups and a carefully defined reference group; (2) to assess the association between fT4/TSH changes throughout pregnancy and hypothyroid symptom levels adjusted for depressive symptoms. Methods: The current study was a longitudinal prospective cohort study in 1800 healthy pregnant women. At each trimester of pregnancy, hypothyroid symptoms were assessed with a 12-item symptom hypothyroidism checklist and depressive symptoms with the Edinburgh Depression Scale. Thyroid dysfunction was defined using the 2.5-97.5th fT4/TSH percentile of thyroid peroxidase antibodies-negative women. Euthyroid controls consisted of women with appropriate fT4 levels within the 10-90th percentile and with a normal TSH level. Hypothyroid symptom mean scores were compared between controls and several thyroid dysfunction subgroups. Growth mixture modeling was performed to evaluate possible longitudinal trajectories of hypothyroid and depressive symptoms. The association between hypothyroid symptom trajectories (adjusted for depression) and fT4/TSH changes was assessed with multivariate logistic regression analysis. Results: Women with overt hypothyroidism (fT4 < 2.5th, TSH >97.5th) and hypothyroxinemia (fT4 < 2.5th, TSH: 2.5-97.5th) showed higher hypothyroid symptom levels compared with the euthyroid controls and women with subclinical hypothyroidism (SCH, fT4: 2.5-97.5th, TSH >97.5th), because 82% of these SCH women had fT4 levels in the euthyroid range. Two groups of hypothyroid and depressive symptoms were defined: a persistently low and persistently high symptom group. fT4 decreased in 98% of the women from the first to third trimester and per unit pmol/L fT4 decrease (not TSH increase), the likelihood to present persistently high hypothyroid symptoms increased with 46%, adjusted for depression. Conclusions: A properly defined euthyroid control group distinguishes women with hypothyroid symptoms. An fT4 decrease toward end term is associated with persistently high hypothyroid symptom levels. Clinicians should be aware of the importance of fT4 stratification in SCH women.


Assuntos
Hipotireoidismo , Doenças da Glândula Tireoide , Feminino , Gravidez , Humanos , Tiroxina , Tireotropina , Iodeto Peroxidase , Estudos Prospectivos , Hipotireoidismo/diagnóstico , Testes de Função Tireóidea , Doenças da Glândula Tireoide/complicações
14.
J Clin Endocrinol Metab ; 107(10): 2925-2933, 2022 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-35861700

RESUMO

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.


Assuntos
Iodeto Peroxidase , Tiroxina , Feminino , Humanos , Gravidez , Valores de Referência , Testes de Função Tireóidea , Glândula Tireoide , Tireotropina
15.
Environ Int ; 167: 107420, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35870378

RESUMO

OBJECTIVES: To investigate the association of exposure to per- and polyfluoroalkyl substances (PFAS) during early pregnancy with markers of the maternal thyroid system. METHODS: Serum concentrations of seven PFAS as well as thyroid stimulating hormone (TSH), free and total thyroxine (FT4 and TT4), free and total triiodothyronine (FT3 and TT3) were measured in pregnant women in early pregnancy in the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy (SELMA) study. Outcomes were concentrations of TSH and thyroid hormones, FT4/FT3 or TT4/TT3 ratios, TSH/FT4 ratio as a marker of the negative feedback loop, TT4/FT4 or TT3/FT3 ratios as markers of the binding of thyroid hormones to binding proteins. RESULTS: The study population comprised 2,008 women with median (95% range) gestational age of 10 (6-14) weeks. There was no association between PFAS and TSH. Higher PFNA, PFDA, PFHpA and PFOA levels were associated with a higher FT4 (largest effect estimate for PFDA: ß [95% CI]: 0.27 [0.10 to 0.45], P = 0.002). Higher PFUnDA levels, but no other PFAS, were associated with a lower FT3 (ß [95% CI]: -0.05 [-0.09 to -0.01], P = 0.005). Higher PFUnDA levels were associated with lower TT4 (ß [95% CI]: -1.58 [-3.07 to -0.09]) and there was an inverted U-shaped association of PFOS with TT4 (P = 0.03). Higher PFDA, PFUnDA, PFHpA levels were associated with a lower TT3. Overall, higher PFAS concentrations were associated with a higher FT4/FT3 ratio and a higher TT4/TT3 ratio. There was no association of PFAS with the TSH/FT4 ratio. Higher concentrations of several PFAS were associated with lower TT4/FT4 and TT3/FT3 ratios. CONCLUSIONS: These findings translate results from experimental studies suggesting that exposure to PFAS may interfere with the thyroid system during pregnancy. Further experimental studies should take into account human evidence to better understand the potential underlying mechanisms of thyroid disruption by PFAS exposure.


Assuntos
Asma , Doença Ambiental , Fluorocarbonos , Hipersensibilidade , Criança , Feminino , Homeostase , Humanos , Lactente , Gravidez , Suécia , Glândula Tireoide , Hormônios Tireóideos , Tireotropina , Tiroxina , Tri-Iodotironina
16.
Environ Int ; 157: 106795, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34358912

RESUMO

BACKGROUND: The extent of thyroid disruptive effects of phthalates during pregnancy remains unclear. AIM: To investigate the association of maternal urinary phthalates with markers of the thyroid system during early pregnancy. METHODS: Urinary concentrations of phthalate metabolites and serum concentrations of thyroid stimulating hormone (TSH), free and total thyroxine (FT4 and TT4) and free and total triiodothyronine (FT3 and TT3) were measured in pregnant women in early pregnancy in the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy study (2007-ongoing), a population-based prospective cohort. RESULTS: In the 1,996 included women, higher di-ethyl-hexyl phthalate (DEHP) metabolites were associated with a lower FT4 (ß [SE] for the molar sum: -0.13 [0.06], P = 0.03) and a higher TSH/FT4 ratio (0.003 [0.001], P = 0.03). Higher concentrations of di-iso-nonyl phthalate (DINP) metabolites were associated with a lower TT4 (ß [SE] for the molar sum: 0.93 [0.44], P = 0.03) as well as with lower TT4/FT4 and TT4/TT3 ratios. Higher metabolites of both dibutyl and butyl-benzyl phthalate (DBP and BBzP) were associated with lower T4/T3 ratio (free and total) and higher FT4/TT4 and FT3/TT3 ratios. A higher diisononyl cyclohexane dicarboxylate (DINCH) metabolite concentration was associated with a higher TT3. CONCLUSIONS: These results translate results from experimental studies suggesting that exposure to phthalates may interfere with the thyroid system during pregnancy. This is also true for compounds that have been introduced to replace known disruptive phthalates. Further experimental studies should take into account the human evidence to better investigate the potential underlying mechanisms of thyroid disruption by phthalates.


Assuntos
Ácidos Ftálicos , Glândula Tireoide , Criança , Exposição Ambiental , Feminino , Humanos , Ácidos Ftálicos/toxicidade , Gravidez , Estudos Prospectivos , Testes de Função Tireóidea , Hormônios Tireóideos
17.
Oncotarget ; 11(27): 2660-2668, 2020 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-32676167

RESUMO

Neuron-specific enolase (NSE) is a well-known biomarker for the diagnosis, prognosis and treatment monitoring of small-cell lung cancer (SCLC). Nevertheless, its clinical applicability is limited since serum NSE levels are influenced by hemolysis, leading to falsely elevated results. Therefore, this study aimed to develop a hemolysis correction equation and evaluate its role in SCLC diagnostics. Two serum pools were spiked with increasing amounts of hemolysate obtained from multiple individuals. A hemolysis correction equation was obtained by analyzing the relationship between the measured NSE concentration and the degree of hemolysis. The equation was validated using intentionally hemolyzed serum samples, which showed that the correction was accurate for samples with an H-index up to 30 µmol/L. Correction of the measured NSE concentration in patients suspected of lung cancer caused an increase in AUC and a significantly lower cut-off value for SCLC detection when compared to uncorrected results. Therefore, a hemolysis correction equation should be used to correct falsely elevated NSE concentrations. Results of samples with an H-index above 30 µmol/L should not be reported to clinicians. Application of the equation illustrates the importance of hemolysis correction in SCLC diagnostics and questions the correctness of the currently used diagnostic cut-off value.

18.
Psychol Med ; 50(2): 229-236, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30696502

RESUMO

BACKGROUND: The aetiology of nausea and vomiting during pregnancy (NVP) is multifactorial, but the relative contribution of biological and psychological determinants is insufficiently understood. We examined the association of human chorionic gonadotropin (hCG), thyroid hormones (thyroid-stimulating hormone and thyroxin) and psychological factors with NVP. METHODS: Blood chemistry and psychological measures were obtained in 1682 pregnant women participating in the Holistic Approach to Pregnancy and the first Postpartum Year (HAPPY) study between 12 and 14 weeks of gestation. The presence of NVP was measured using the Pregnancy-Unique Quantification of Emesis scale. Depressive symptoms were assessed using the Edinburgh Depression Scale. Multivariable logistic regression analyses were used to investigate the independent role of hCG, thyroid hormones and depression as related to NVP, adjusting for age, body mass index, education, parity, smoking status, unplanned pregnancy and history of depression. RESULTS: Elevated levels of NVP were observed in 318 (18.9%) participants. High hCG levels [odds ratio (OR) = 1.47, 95% confidence interval (CI) = 1.11-1.95], elevated depressive symptoms in the first trimester (OR = 1.67, 95% CI = 1.15-2.43) and a history of depression (OR = 1.53, 95% CI = 1.11-2.11) were independently related to high NVP. Multiparity (OR = 1.47, 95% CI = 1.12-1.92) and younger age (OR = 0.91, 95% CI = 0.87-0.94) were also associated with high NVP, whereas (sub)clinical hyperthyroidism was not related to high NVP. CONCLUSIONS: The current study is the first to demonstrate that a combination of hCG hormone and psychological factors are independently related to nausea and vomiting during early pregnancy.


Assuntos
Depressão/epidemiologia , Náusea/epidemiologia , Complicações na Gravidez/epidemiologia , Vômito/epidemiologia , Adulto , Feminino , Humanos , Hipertireoidismo/epidemiologia , Modelos Logísticos , Análise Multivariada , Náusea/psicologia , Países Baixos/epidemiologia , Gravidez , Complicações na Gravidez/psicologia , Primeiro Trimestre da Gravidez , Tireotropina/sangue , Tiroxina/sangue , Vômito/psicologia , Adulto Jovem
19.
Thyroid ; 29(11): 1660-1668, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31524090

RESUMO

Background: Severe maternal iodine deficiency can impact fetal brain development through effects on maternal and/or fetal thyroid hormone availability. The effects of mild-to-moderate iodine deficiency on thyroid function are less clear. The aim was to investigate the association of maternal urinary iodine concentration corrected for creatinine (UI/Creat) with thyroid function and autoantibodies in a mild-to-moderate iodine-deficient pregnant population. Methods: This study was embedded within the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy (SELMA) study. Clinical reference ranges were determined by the 2.5th and 97.5th population-based percentile cutoffs. The associations of UI/Creat with thyrotropin (TSH), free thyroxine (fT4), free triiodothyronine (fT3), total T4 (TT4), and total T3 (TT3) were studied using multivariable linear regression in thyroid peroxidase antibody (TPOAb)-negative women. The association of UI/Creat with TPOAb and thyroglobulin antibody (TgAb) positivity was analyzed using multivariable logistic regression. Results: Urinary iodine and thyroid function were measured at a median (95% range) gestational age of 10 (6-14) weeks in 2009 women. The median (95% range) UI/Creat was 85 µg/g (36-386) and the UI/Creat was below 150 µg/g in 80.1% of women. Reference ranges did not differ substantially by UI/Creat. A lower UI/Creat was associated with a lower TSH (p = 0.027), a higher TT4 (p = 0.032), and with a corresponding trend toward slightly higher fT4 (p = 0.081), fT3 (p = 0.079), and TT3 (p = 0.10). UI/Creat was not associated with the fT4/fT3 (p = 0.94) or TT4/TT3 ratios (p = 0.63). Women with a UI/Creat of 150-249 µg/g had the lowest prevalence of TPOAb positivity (6.1%), while women with a UI/Creat of <150 µg/g had a higher prevalence (11.0%, odds ratio [OR] confidence interval [95% CI] 1.84 [1.07-3.20], p = 0.029). Women with a UI/Creat ≥500 µg/g showed the highest prevalence and a higher risk of TPOAb positivity, however, only a small proportion of women had such a UI/Creat (12.5%, OR, [95% CI] 2.36 [0.54-10.43], p = 0.26). Conclusions: We could not identify any meaningful differences in thyroid function reference ranges. Lower iodine availability was associated with a slightly lower TSH and a higher TT4. Women with adequate iodine intake had the lowest risk of TPOAb positivity.


Assuntos
Asma/epidemiologia , Hipersensibilidade/epidemiologia , Iodo/deficiência , Iodo/urina , Testes de Função Tireóidea , Adulto , Autoanticorpos/análise , Criança , Estudos de Coortes , Meio Ambiente , Feminino , Humanos , Recém-Nascido , Iodeto Peroxidase/sangue , Estudos Longitudinais , Mães , Estado Nutricional , Gravidez , Prevalência , Valores de Referência , Suécia/epidemiologia , Hormônios Tireóideos/sangue , Adulto Jovem
20.
Environ Int ; 122: 256-262, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30477815

RESUMO

INTRODUCTION: Exposure to the antimicrobial agent triclosan is ubiquitous. Research in animals shows that triclosan can cause decreases in thyroxine concentrations. However, the potential effects of triclosan on thyroid function in humans are unclear. OBJECTIVE: To estimate the association between urinary triclosan concentrations and serum thyroid function biomarkers in women seeking assisted reproduction treatment in the Environment and Reproductive Health (EARTH) Study. METHODS: We conducted a cross-sectional study of 317 women enrolled in the EARTH Study, a prospective preconception cohort that recruits Boston area couples. Using samples collected at study entry, we quantified urinary triclosan and serum thyroid function biomarker concentrations, specifically free and total thyroxine and triiodothyronine, thyroid-stimulating hormone (TSH), and thyroid antibodies. We estimated covariate-adjusted differences in thyroid function biomarkers per 10-fold increase in triclosan using linear regression models. We examined effect modification by body mass index (BMI) and infertility diagnosis. RESULTS: The median urinary triclosan concentration was 7.8 µg/L (IQR: 3.0-59 µg/L). Each 10-fold increase in triclosan was inversely associated with free triidothyronine (T3) (ß: -0.06 pg/mL; 95% CI: -0.1, -0.01), thyroperoxidase antibody (TPOAb) (-10%; 95% CI: -19, -0.4), and thyroglobulin antibody (TgAb) (-12%; 95% CI: -23,0.9) concentrations. BMI and infertility diagnosis modified the association of triclosan with free T3 and TPOAb, respectively. CONCLUSION: Urinary triclosan concentrations were inversely associated with specific serum thyroid function biomarkers in this cohort, suggesting that triclosan may affect thyroid homeostasis and autoimmunity.


Assuntos
Autoanticorpos/sangue , Tireotropina/sangue , Triclosan/urina , Biomarcadores/sangue , Boston/epidemiologia , Estudos Transversais , Feminino , Humanos , Estudos Prospectivos
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