Gestation-specific Reference Intervals Research Articles

Assesing the effect of thyroid dysfunction during pregnancy on maternal and neonatal outcomes with guidelines and population-based gestation-specific reference intervals

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Accurate interpretation of thyroid dysfunction during pregnancy: should we continue to use published guidelines instead of population-based gestation-specific reference intervals for the thyroid-stimulating hormone (TSH)?

BackgroundConsidering the changes in thyroid physiology associated with pregnancy and poor outcomes related to abnormal maternal thyroid function, international guidelines recommend using population-based trimester-specific reference intervals (RIs) for thyroid testing. If these RIs are not available in the laboratory, implementing recommended fixed cut-off values globally is still controversial. To address this issue, we aimed to establish appropriate RI of thyroid-stimulating hormone (TSH) in pregnant Turkish women for our laboratory and compare the prevalence of thyroid dysfunction based on the established and recommended criteria.MethodsOf 2638 pregnant women, 1777 women followed in the obstetric outpatient were enrolled in the reference interval study after applying exclusion criteria related to medical and prenatal history. A retrospective study was conducted by collecting data from July 2016 to March 2019. Serum TSH was measured by UniCel DxI 800 Immunoassay System (Beckman Coulter Inc., Brea, CA, USA). The study design relied on two approaches in order to classify pregnant women: trimester-specific and subgroup-specific; the latter involved dividing each trimester into two subgroups: T1a, T1b, T2a, T2b, T3a, T3b. The lower and upper limits of the RIs were derived by the parametric method after normalizing the data distribution using the modified Box-Cox power transformation method.ResultsThe lowest TSH value was detected at 8-12 weeks in early pregnancy, and the median value of TSH in the T1b subgroup was significantly lower than the T1a subgroup (P < 0.05). TSH levels showed a gradual trend of increase along with the pregnancy and increased significantly in the T2a, T2b, and T3b subgroups compared to the preceding subgroups (P < 0.05). Compared to the diagnostic criteria recommended by American Thyroid Association (ATA), the prevalence of thyroid dysfunction was significantly different from the established trimester- and subgroup-specific RIs throughout the pregnancy (P < 0.001).ConclusionsWe conclude that establishing gestation- and laboratory-specific RIs, especially for TSH, is essential for diagnosing thyroid disorders in pregnancy, and the recommended universal cut-off values, which may contribute to the risk of a misdiagnosis or a missed diagnosis, should be taken with caution in the clinical setting. However, regarding the fluctuation of thyroid function tests throughout pregnancy, trimester-specific RIs are insufficient, and implementing split phases is required.

First-Trimester Reference Intervals for Thyroid Function Testing among Women Screened at a Tertiary Care Hospital in India.

Objectives Due to differences in the method of assay and population-specific factors, each laboratory needs to establish its own gestation-specific reference intervals (GRIs) for thyroid hormones. Materials and Methods Three-hundred forty-one women with less than 14 weeks gestation were screened at a tertiary care hospital in Chhattisgarh, India. Serum levels of thyroid-stimulating hormone (TSH), free thyroxine (fT4), and thyroid peroxidase antibody (anti-TPO) were measured using an ADVIA Centaur XP immunoassay. GRIs (2.5th and 97.5th percentiles) were determined for TSH and fT4. TSH and fT4 concentrations were converted to multiples of the median (MoM) values. Effect of maternal age, gestational age, and maternal weight was analyzed.Statistical Analysis Quantitative variables were expressed as means and standard deviations (SD), and qualitative variables were expressed as frequencies and percentages. Normality of the data was checked using the Kolmogorov–Smirnov test. Values that were normally distributed were expressed only as means and SD. Those that were not normally distributed were expressed as medians and interquartile range. For all statistical analysis, p < 0.05 was considered as statistically significant. Results First-trimester GRI was 0.245 to 4.971 mIU/L for TSH, 10.2 to 18.9 pmol/L for fT4, and 27.0 to 56.89 kIU/L for anti-TPO. There was no significant difference in the mean serum TSH ( p = 0.920), fT4 ( p = 0.714), or anti-TPO ( p = 0.754) values among women in 4 to 7th week and 7 to 14th week of gestation. The 1st and 99th centile MoMs were 0.03 and 4.09 for TSH and 0.66 and 1.39 for fT4. There was a significant positive correlation between the maternal weight and TSH MoM values ( p = 0.027, r = 0.120). Conclusion These laboratory- and first-trimester-specific GRI for TSH and fT4 shall help in proper diagnosis and treatment of subclinical thyroid dysfunctions. TSH and fT4 MoM values can be used to indicate high or low values in a quantitative manner independent of the reference ranges and may be used by other laboratories.

Trimester-specific reference intervals of thyroid function tests in Turkish pregnants

Physiological changes in hormone levels occur in thyroid gland during pregnancy. Screening of the thyroid hormone levels and determining trimester-specific reference intervals in pregnancy are important. Guidelines recommend the use of trimester-specific reference ranges for each country. The aim of this study is to determine trimester-specific thyroid function reference intervals for pregnancy in Turkish population. In total, 5000 patients were screened out of which 1258 patients have all of fT3, fT4 and TSH levels measured, were included in the study. Patients were grouped as follows: 482 women were in first trimester, 361 women were in second trimester, and 415 women were in third trimester. All analyses were performed by means of chemiluminescence methods (Liaison®; DiaSorin S.p.A., Saluggia, Italy). The TSH reference intervals were 0.005–3.65, 0.01–3.63, and 0.2–3.46 mIU/L at the first, the second, and the third trimesters of pregnancy, respectively. The fT4 reference intervals were 0.72–1.79, 0.71–1.26, and 0.65–1.12 ng/dL at the first, the second, and the third trimesters, respectively. The fT3 reference intervals were 2.45–4.03, 2.37–3.85, and 2.31–3.77 ng/dL at the first, the second, and the third trimesters, respectively. It is crucial to determine population- and gestational-specific reference intervals for trustworthy treatment of pregnants.

The Reference Intervals of Thyroid Hormones for Pregnant Women in Zhejiang Province.

Gestation-specific reference intervals for thyroid hormones are used to estimate thyroid function in pregnant women. This study was to establish the reference intervals for pregnant women in Zhejiang province, China. A total of 9038 cases were recruited. The values of thyroid-stimulating hormone (TSH), free thyroxine, free triiodothyronine, total thyroxine, and total triiodothyronine were determined by Beckman Coulter DxI-800 analyzers. Our results indicated that the level of TSH declined in the first trimester and then rose as pregnancy progressed. Conversely, the level of free triiodothyronine rose in the first trimester and then declined. The ranges of free thyroxine kept the decreasing trend crossing the gestation period. For total triiodothyronine, the ranges increased as pregnancy progressed and declined in the third trimester. The variation trends of total triiodothyronine and total thyroxine were similar. Our data confirmed the importance of the reference intervals of thyroid hormones for pregnant women.

Development of gestation-specific reference intervals for thyroid hormones in normal pregnant Northeast Chinese women: What is the rational division of gestation stages for establishing reference intervals for pregnancy women?

BackgroundA laboratory- and region-specific trimester-related reference interval for thyroid hormone assessment of pregnant women was recommended. Whether the division by trimester is suitable requires verification. Here, we tried to establish appropriate reference intervals of thyroid-related hormones and antibodies for normal pregnant women in Northeast China. MethodsA total of 947 pregnant women who underwent routine prenatal care were grouped via two methods. The first method entailed division by trimester: stages T1, T2, and T3. The second method entailed dividing T1, T2, and T3 stages into two stages each: T1-1, T1-2, T2-1, T2-2, T3-1, and T3-2. Serum levels of TSH, FT3, FT4, Anti-TPO, and Anti-TG were measured by three detection systems. ResultsNo significant differences were found in TSH values between T1-1 group and the non-pregnant women group. However, the TSH value of the T1-1 group was significantly higher than that of T1-2 group (P<0.05). The TSH values in stage T3-2 increased significantly compared to those in stage T3-1 measured by three different assays (P<0.05). FT4 and FT3 values decreased significantly in the T2-1 and T2-2 stages compared to the previous stage (P<0.05). The serum levels of Anti-TPO and Anti-TG were not having significant differences between the six stages. ConclusionThe diagnosis and treatment of thyroid dysfunction during pregnancy should base on pregnancy- and method-specific reference intervals. More detailed staging is required to assess the thyroid function of pregnant women before 20 gestational weeks.

Gestation-specific reference intervals for thyroid function tests and the clinical significance for thyroid function monitoring through different periods of pregnancy

Objective To investigate the gestation-specific reference intervals (GRIs) and dynamic changes of thyroid function at different gestational ages in Chongqing. Methods Combining self-sequential longtitudinal with cross-sectional study, the serum samples from 640 pregnant women with different gestational age were collected from June 2014 to September 2015 in the Third Military Medical University. The free triiodothyronine (FT3), free thyroxine (FT4), thyroglobulin (TG), thyroid-stimulating hormone (TSH), thyroid peroxidase antibody (TPOAb), and antithyroglobulin antibody (TGAb) were detected by the direct chemiluminescence method. According to China Guideline for the diagnosis and treatment of thyroid disease in pregnancy and postpartum in 2012, the reference interval of the thyroid function was calculated. The data were analyzed by Chi square test. Results Established GRIs of thyroid function during pregnancy in Chongqing: The GRIs was 3.68-5.59 pmol/L for FT3, 9.34-17.02 pmol/L for FT4, 0.18-5.26 mIU/L for TSH in 6-9+ 6 weeks of pregnancy; the GRIs was 3.69-6.03 pmol/L for FT3, 8.42-15.75 pmol/L for FT4、0.09-4.85 mIU/L for TSH in 10-13+ 6 weeks of pregnancy; the GRIs was 3.24-5.46 pmol/L for FT3, 6.50-14.24 pmol/L for FT4, 0.11-5.13 mIU/L for TSH in 14-27+ 6 weeks of pregnancy; the GRIs was 3.06-5.05 pmol/L for FT3, 6.12-11.69 pmol/L for FT4, 0.75-3.67 mIU/L for TSH in 30-34 weeks of pregnancy; the GRIs was 2.96-5.00 pmol/L for FT3, 6.26-11.36 pmol/L for FT4, 0.84-5.54 mIU/L for TSH in 36-40 weeks of pregnancy. Screening by GRIs, the prevalence of thyroid dysfunction was 8.75% (46), however, the prevalence was 37.07% (195) in according with the guidelines, χ2=120.5, P=0.000. The overdiagnosis rate was 28.32%(149/526). Using the guidelines of thyroid disease and our GRIs, the thyroid disease was found 116 (22.05%) and 30(5.70%) in the first screening. Moreover, the thyroid disease was found 79(19.27%) and 10(3.23%) during the repeat screening in the normal population. Conclusions Using the GRIs for thyroid function tests in normal singleton pregnant women could reduce the risk of over diagnosis. The detection rate of repeat screening of TPOAb negative patients was close to the first screening detection rate, and repeated screening could reduce the risk of missed diagnosis for thyroid dysfunction in pregnancy women.(Chin J Lab Med, 2016, 39: 511-515) Key words: Pregnancy; Reference values; Hypothyroidism; Thyroxine

Gestation specific reference intervals for thyroid function tests in pregnancy.

Thyroid function tests are frequently assessed during pregnancy to evaluate thyroid dysfunction or to monitor pre-existing thyroid disease. However, using non-pregnant reference intervals can lead to misclassification. International guidelines recommended that institutions should calculate their own pregnancy-specific reference intervals for free thyroxine (FT4), free triiodothyronine (FT3) and thyroid-stimulating hormone (TSH). The objective of this study is to establish gestation-specific reference intervals (GRIs) for thyroid function tests in pregnant Turkish women and to compare these with the age-matched non-pregnant women. Serum samples were collected from 220 non-pregnant women (age: 18-48), and 2460 pregnant women (age: 18-45) with 945 (39%) in the first trimester, 1120 (45%) in the second trimester, and 395 (16%) in the third trimester. TSH, FT4 and FT3 were measured using the Abbott Architect i2000SR analyzer. GRIs of TSH, FT4 and FT3 for first trimester pregnancies were 0.49-2.33 mIU/L, 10.30-18.11 pmol/L and 3.80-5.81 pmol/L, respectively. GRIs for second trimester pregnancies were 0.51-3.44 mIU/L, 10.30-18.15 pmol/L and 3.69-5.90 pmol/L. GRIs for third trimester pregnancies were 0.58-4.31 mIU/L, 10.30-17.89 pmol/L and 3.67-5.81 pmol/L. GRIs for TSH, FT4 and FT3 were different from non-pregnant normal reference intervals. TSH levels showed an increasing trend from the first trimester to the third trimester, whereas both FT4 and FT3 levels were uniform throughout gestation. GRIs may help in the diagnosis and appropriate management of thyroid dysfunction during pregnancy which will prevent both maternal and fetal complications.

Gestation-specific reference intervals for comprehensive spot urinary steroid hormone metabolite analysis in normal singleton pregnancy and 6 weeks postpartum.

BackgroundNormal pregnancy depends on pronounced adaptations in steroid hormone concentrations. Although in recent years, the understanding of these hormones in pregnancy has improved, the interpretation is hampered by insufficient reference values. Our aim was to establish gestation-specific reference intervals for spot urinary steroid hormone levels in normal singleton pregnancies and 6 weeks postpartum.MethodsCross-sectional multicentre observational study. Women recruited between 2008 and 2013 at 3 University Hospitals in Switzerland (Bern), Scotland (Glasgow) and Austria (Graz). Spot urine was collected from healthy women undergoing a normal pregnancy (age, 16–45 years; mean, 31 years) attending routine antenatal clinics at gestation weeks 11, 20, and 28 and approximately 6 weeks postpartum. Urine steroid hormone levels were analysed using gas-chromatography mass spectrometry. Creatinine was also measured by routine analysis and used for normalisation.ResultsFrom the results, a reference interval was calculated for each hormone metabolite at each trimester and 6 weeks postpartum. Changes in these concentrations between trimesters and postpartum were also observed for several steroid hormones and followed changes proposed for index steroid hormones.ConclusionsNormal gestation-specific reference values for spot urinary steroid hormones throughout pregnancy and early postpartum are now available to facilitate clinical management and research approaches to steroid hormone metabolism in pregnancy and the early postpartum period.

Gestational thyroid reference intervals in antibody-negative Chinese women

ObjectivesThe aim of this study is to establish gestation-specific reference intervals (GRIs) for thyroid function assays in pregnant Chinese women with ARCHITECT and compare them to other GRI studies. Design and methodThyroid antibody negative pregnant Chinese women were enrolled and followed to establish GRIs for thyroid function by use of the Abbott ARCHITECT i2000SR analyzer (N=1409). Samples from 360 non-pregnant Chinese women served as controls. ResultsGRIs of thyroid-stimulating hormone, free thyroxine and free triiodothyronine for first trimester pregnancies were 0.16–3.78mIU/L, 10.9–17.7pmol/L and 2.9–5.0pmol/L, respectively. GRIs for second trimester pregnancies were 0.34–3.51mIU/L, 9.3–15.2pmol/L and 2.9–4.6pmol/L. GRIs for third trimester pregnancies were 0.34–4.32mIU/L, 7.9–14.1pmol/L and 2.9–4.5pmol/L. ConclusionsOur thyroid GRIs were different from those in other Chinese studies generated on other analyzers, but were similar to a Swiss study using the same analyzer. These data should prove useful for the interpretation of thyroid function assays among pregnant women measured on the Abbott analyzer.

Apparent diffusion coefficient measurements of the fetal brain during the third trimester of pregnancy: how reliable are they in clinical practice?

The objective of this study was to determine the reproducibility, the inter-hemispheric difference and the reference apparent diffusion coefficient (ADC) values of the fetal brain according to gestational age. One hundred and one normal fetal brain (29.4-38.4 weeks) were analysed with diffusion-weighted MR imaging. ADC was measured in frontal white matter (FWM), occipital white matter (OWM), centrum semi-ovale (CSO), basal ganglia (BG), cerebellar hemisphere (CBM) and pons. ADC ratios (fronto-occipital, fronto-cerebellar and occipito-cerebellar) were calculated. Inter-observer reproducibility was assessed on 27 studies, using intra-class correlation coefficient and Bland-Altman plot. Inter-hemispheric difference was evaluated with Bland-Altman plot. Gestation-specific reference intervals were estimated for each brain region. Inter-observer bias was near zero. Limits of agreement (LOA) were clinically acceptable (-0.17; 0.20 to -0.38; 0.31 × 10(-3) mm(2) /s) for all brain regions except for CSO and pons. Inter-hemispheric bias was near zero. Smallest LOA were for FWM (±0.09 mm(2) /s) and BG (±0.019 mm(2) /s). ADC values decreased, whereas ADC ratio increased with gestational age, reflecting normal maturation. Fronto-occipital, fronto-cerebellar and occipito-cerebellar ratios were consistently above 0.8, 1 and 1, respectively. The fetal brain regions with the highest reproducibility and smallest inter-hemispheric differences are the frontal, occipital, cerebellar white matter and BG. ADC ratio could be useful to assess differential temporo-spatial maturation.

Gestation-specific reference intervals for fetal cardiac Doppler indices from 12 to 40 weeks of gestation

We aimed to establish gestation age specific reference intervals for Doppler indices of fetal cardiac function from 12 to 40 weeks of pregnancy. In a cross-sectional observational study of singleton pregnancies, examinations were performed in 221 women evenly distributed across each week of pregnancy. Blood flow through the four cardiac valves was examined with Doppler. For the atrioventricular valves, velocity and duration of early (E) and atrial (A) waves and the interval (a) between E/A complexes was recorded. For the outflow valves, the duration (b), peak and average velocity of flow in systole was measured. Myocardial performance index (MPI) was calculated as (a - b)/b. Outlet valve diameters were measured and cardiac outputs were calculated. Gestation age specific ranges were constructed for all these parameters. We demonstrated that the cardiac output, peak systolic and time-averaged velocity increase with advancing gestation. However the MPI and E/A ratios show little change across gestation. Fetal cardiac physiology can be studied and Doppler indices reliably measured as early as the late first trimester of pregnancy. Establishing gestation age specific ranges for various cardiac indices throughout pregnancy will help the study of development of fetal cardiac function.

Gestation‐specific reference intervals for right and left ventricular ejection force from 12 to 40 weeks of gestation

Ejection force of the fetal cardiac ventricles has previously been described from 18weeks of gestation. We aimed to establish gestation-specific reference intervals for ventricular ejection force (VEF) from 12 to 40weeks of pregnancy. In a cross-sectional observational study of singleton pregnancies, examinations were performed in 236 women evenly distributed across each week of pregnancy from 12 to 40weeks. Each mother was scanned once. For the aortic and pulmonary valves, the time to peak velocity (TPV) and the average (TAV) and peak flow velocity in systole (PSV) was measured. For each we averaged values from three consecutive complexes. The outlet valve diameters were measured and the VEF on both the right and left sides were calculated using the formula VEF=(1.055×valve area×time to peak velocity×TAV)×(PSV/TPV) where 1.055 represents the density of blood. Measurements were repeated in 40 women to assess intraobserver reproducibility and in 19 women for interobserver variability. We present reference intervals for right and left VEF. We demonstrated that the ventricular force on both right and left sides increases with advancing gestational age. Fetal cardiac physiology can be studied and Doppler indices reliably measured as early as the late first trimester of pregnancy. Ventricular ejection force and its relationship with fetal growth could be explored in future studies and this may eventually provide better understanding of changes which may predispose to adult cardiac disease.

Assessment of thyroid function during pregnancy: the advantage of self-sequential longitudinal reference intervals

IntroductionTo evaluate clinical value of a new self-sequential longitudinal reference intervals of thyroid function during pregnancy.Material and methodsWe established two different series of reference intervals: self-sequential longitudinal reference intervals (SLRI) and general gestation-specific reference intervals (GSRI). For SLRI, the serum of 301 cases were collected five times in every case throughout the gestation. For GSRI, A total of 1455 subjects included in the study. We collected the serum respectively at various trimesters. We used TSH of both reference intervals to screen 1744 pregnant women, and compared the percentage of potential misclassification.ResultsBoth SLRI and GSRI differed substantially from that for non-pregnant women (p < 0.05). There are similar fluctuations of serum TSH, FT4 and TPO-Ab during normal pregnancy. Although there were no significant differences in most reference intervals between SLRI and GSRI. But the IQR of SLRI were usually smaller than GSRI , especially in 1st trimester. Two hundred and fifty two women (14.4%) at various trimesters whose serum TSH concentration was within SLRI would be misclassified, while 23 women (1.3%) with a TSH concentration outside limit would not be identified. 0.11-3.84% women would got thyroid diseases during pregnancy. Subclinical hypothyroidism is most common maternal thyroid disorders.ConclusionsThe SLRI can reflected the changes of thyroid function realistically, and can be used to decrease the percentage of potential misclassification of thyroid dysfunction during pregnancy. Screening for thyroid dysfunction of pregnant women is recommended and important.

Gestation-specific reference intervals for fetal cardiac Doppler indices for the left heart from 12 to 40 weeks of gestation

ObjectivesThe authors aimed to establish gestation specific reference intervals for Doppler indices of fetal cardiac function from 12 to 40 weeks of pregnancy.MethodsIn a cross-sectional observational study of singleton pregnancies,...

Gestation-specific reference intervals for fetal cardiac Doppler indices for the right heart from 12 to 40 weeks of gestation

ObjectivesThe authors aimed to establish gestation specific reference intervals for Doppler indices of fetal cardiac function from 12 to 40 weeks of pregnancy.MethodsIn a cross-sectional observational study of singleton pregnancies,...

Gestation-specific reference intervals for right and left ventricular ejection force from 12 to 40 weeks of gestation

ObjectivesEjection force of the fetal cardiac ventricles has only been assessed from 18 weeks of gestation. Hence, the authors aimed to establish gestation specific reference intervals for ventricular ejection force...

Narrow intra-individual variation of maternal thyroid function in pregnancy based on a longitudinal study on 132 women

Adaptive alterations in maternal physiology cause changes in thyroid hormone levels throughout pregnancy, and precise biochemical evaluation is thus highly dependent on gestation-specific reference intervals and expected intra-individual variation. The aim of the study was the assessment of the intra-individual variation as well as the longitudinal course of thyroid hormones during normal pregnancy and factors that influence the normal reference range for thyroid function. For this purpose, a longitudinal statistical model was applied. In a cohort of 132 pregnant women, serial blood samples were obtained and ultrasound scans were performed throughout pregnancy. Serum levels of TSH, free and total thyroxine (T(4)), free and total triiodothyronine (T(3)) as well as autoantibodies against thyroid peroxidase and thyroglobulin were measured in 979 serum samples. Intra-individual variations of thyroid hormone concentrations were smaller than inter-individual variations (individuality index range: 0.38-0.71). Maternal height was positively associated with free T(4) (FT(4)) (b=0.003; P=0.031) and pre-pregnancy body mass index with T(3) and free T(3) (b=0.017; <0.001 and b=0.007; P<0.001). Smoking was positively associated with T(4) and FT(4), but it was modulated by gestational age. Gestation-specific reference intervals for thyroid function variables from autoantibody-negative participants are presented. In accordance with the data from nonpregnant adults, intra-individual variations of thyroid hormones were smaller than inter-individual variations also during pregnancy. In the evaluation of thyroid function in pregnancy, the individual longitudinal course of thyroid hormones rather than absolute values should be considered. We present a longitudinal model for the prediction of maternal thyroid function tests in pregnant women.

Reference values for thyroid function tests during pregnancy1

Abstract Euthyroid women experience dramatic changes in the demand for thyroid hormone production as early as the first trimester of pregnancy. These adaptations are important for fetal neurodevelopment and organ development as well as maternal health and successful full-term pregnancy. Thyroid disease is the most common endocrine condition in women of childbearing age and leads to complications in approximately 1–2% of all pregnancies. The hypermetabolic state of normal pregnancy makes clinical assessment of thyroid function more difficult and therefore thyroid function often needs to be investigated biochemically. However, physiological changes of pregnancy, including a 50% plasma volume expansion, increased thyroid binding globulin production, and a relative iodine deficiency, implicate that thyroid hormone reference ranges for non-pregnant women may not be appropriate in pregnancy. Therefore, gestation-specific reference intervals assist in appropriate clinical management of thyroid disease in pregnancy to ensure maternal and fetal health.

A study to establish gestation-specific reference intervals for thyroid function tests in normal singleton pregnancy

A study to establish gestation-specific reference intervals for thyroid function tests in normal singleton pregnancy