Clinica Chimica Acta 428 (2014) 96–98
Contents lists available at ScienceDirect
Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim
Letter to the Editor Second trimester thyroid-stimulating hormone, total and free thyroxine reference intervals for the Beckman Coulter Access® 2 platform
Dear Editor: Profound changes in thyroid hormones (THs) occur in the maternal body during pregnancy. These alterations pose a particular challenge for the interpretation of thyroid test results and the diagnosis of thyroid dysfunction in pregnant women. However, it remains vital to recognize maternal thyroid disease (whether hyper- or hypothyroidism), as failure to do so is associated with a litany of complications, including an increased likelihood of pre-eclampsia, placental abruption, spontaneous abortion, prematurity, impaired fetal cerebral development, low neonatal birthweight, and intrauterine growth restriction and death [1–3]. Reference intervals (RIs) found in the inserts of commercial assays are almost always derived from the general population and are not suitable for pregnant females. The U.S. National Academy of Clinical Biochemistry (NACB) [4] and the Endocrine Society [5] have advocated for the use of trimester-specific RIs, while the American Thyroid Association [6] has recommended both trimester- and method-dependent RIs to be developed for thyroid analytes during pregnancy. In addition, such factors as age, ethnicity (including ethnic-related characteristics — for example, dietary patterns), geographical location, and iodine status can not only affect the prevalence of thyroid disease, but also the establishment of TH reference ranges [7,8]. Although pregnancy TH RIs based on several platforms have been published [7,9–15], we are not aware of any reports which describe the RIs for the Beckman Coulter Access® 2 analyzer for the early second trimester, except for a brief abstract [16]. We are therefore publishing our observations from a RI study performed incidentally during an investigation which examined environmental chemical exposures and thyroid hormone physiology in pregnancy (GM Webster et al., manuscript submitted for publication). Specifically, we determined early second trimester RIs for thyroid-stimulating hormone (TSH), total thyroxine (TT4) and free thyroxine (FT4) via serum samples collected from healthy, likely iodine-replete, and predominantly Caucasian pregnant females. TT4 measurements were included because some believe pregnancy-adjusted TT4 (i.e. multiplication of the non-pregnancy TT4 RI by a factor of 1.5) to be a more reliable method of estimating FT4 status in pregnancy [17]. One hundred and fifty-two pregnant women (mean age of 34, range 25–43) living in the Greater Vancouver area (Canada) were enrolled between 2007 and 2008. Inclusion criteria were as previously described [18]; in brief, eligible participants were carrying a singleton pregnancy; had conceived without the use of assisted reproductive technology, fertility drugs, or hormones; had no prior diagnosis of thyroid disease; and were not taking antidepressants or other drugs known to affect TH concentrations [19,20]. In Canada, iodization of table salt has been made mandatory by law since 1949, and a recent national survey has shown an adequate median iodine concentration (1.06 μmol/l) in Canadians [21]. Iodine status in study subjects was monitored via a questionnaire inquiring about the intake of prenatal vitamins and their iodine content; 0009-8981/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.cca.2013.11.006
urinary iodine was not measured. This study was approved by the Institutional Review Board of the University of British Columbia and other participating research centers, and written consent was obtained from all participants. Two 20 ml samples of maternal blood were collected at 15 and 18 week gestational age (GA), respectively, and the separated serum was stored at −80 °C until analysis was performed. TSH, TT4, FT4, and thyroid peroxidase autoantibody (TPOAb) concentrations were measured on the Beckman Coulter Access® 2 assay (Mississauga, ON, Canada). Within- and between-day coefficients of variation (CVs) in our laboratory were within the manufacturer's specifications. Detection limits were 0.003 mIU/l for TSH, 6 nmol/l for TT4, 2.6 pmol/l for FT4, and 0.3 IU/ml for TPOAb. Patients with TPOAb above the upper reference limit (≥9 IU/ml, n = 14 [9.2%]) were excluded from RI determinations. In addition, one subject with a marked elevation in beta human chorionic gonadotropin (β-hCG) concentration and consequent thyrotoxicosis was also omitted from the study. An additional 4 subjects were excluded due to an incomplete data set (final n = 133). All statistical analyses were performed with SPSS (ver 19.0.0, SPSS Inc.). The central 95% RIs were determined non-parametrically for all thyroid analytes. Only maternal serum samples with normal TSH results (n = 124, as defined by a TSH within the central 95th percentile, for both 15 and 18 week GA collections) were used to establish the respective second trimester FT4 and TT4 RIs [9,13,14]. RI medians between 15 and 18 week GA were compared using the Wilcoxon signed-rank test. Pearson's correlation coefficient was used to study the degree of correlation between maternal TSH, TT4, and FT4 concentrations. A P-value of b0.05 was considered to be statistically significant. Demographics of the study participants (mean age of 34, range 25–43; 82% Caucasians) were previously published [18]. Table 1 lists the RIs for TSH, TT4 and FT4 derived in this study, the RIs provided by the manufacturer, and any second trimester TH RIs available in the literature for the Beckman Coulter Access® 2 assay. Note that the manufacturer provides both second trimester specific RIs and adult (non-pregnant) RIs for FT4, but only adult (non-pregnant) RIs for TT4 and TSH. Considering data from this study, the median maternal FT4 and TT4 concentrations were significantly higher at 15 week than at 18 week GA (FT4: 9.50 pmol/l vs. 8.45 pmol/l, P b 0.001; TT4: 125.19 nmol/l vs. 119.39 nmol/l, P b 0.001). In contrast, median maternal TSH concentrations were similar between the two time points (TSH: 1.28 mIU/l vs. 1.25 mIU/l, P = NS). A weak inverse correlation was noted between maternal FT4 and TSH at 18 week GA (r = − 0.226, P = 0.012), but not at 15 week GA (r = − 0.142, P = 0.116). An inverse correlation between maternal TT4 and TSH observed at 15 week GA did not reach statistical significance (r = − 0.167, P = 0.063); no correlation was observed at 18 week GA (r = 0.011, P = NS). As expected, all three thyroid analytes were highly correlated between 15 week and 18 week GA within women (FT4: r = 0.748, P b 0.001; TT4: r = 0.651, P b 0.001; TSH: r = 0.741, P b 0.001). Next, we compared the RIs derived in this study to the manufacturer's RIs, as well as to the FT4 RI determined by Jarrige et al. [16] (Table 1). Jarrige et al.'s second trimester data were derived from 139 pregnant females (iodine status unspecified), with exclusion of
Letter to the Editor
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Table 1 Central 95% reference intervals for TSH, TT4, and FT4 in adult pregnant females measured on the Beckman Coulter Access® 2 platform.
FT4 (pmol/l) n = 124
TT4 (nmol/l) n = 124 TSH (mIU/l) n = 133
15 week GA (this study) 18 week GA (this study) Second trimester (Jarrige et al. [16]) Second trimester (manufacturer) Non-pregnant (manufacturer) 15 week GA (this study) 18 week GA (this study) Non-pregnant (manufacturer) 15 week GA (this study) 18 week GA (this study) Non-pregnant (manufacturer)
Lower limit (95% CI)
Median
Upper limit (95% CI)
7.61 (7.30–8.00) 6.80 (5.88–7.10) 5.84 (CI N/A) 5.79 (5.19–6.14)a 7.86 (7.00–8.57) 92.62 (78.98–104.36) 85.17 (66.69–94.56) 78.38 (CI N/A) 0.25 (0.04–0.55) 0.33 (0.17–0.51) 0.34 (CI N/A)
9.50 8.45 N/A N/A N/A 125.19 119.39 107.59 1.28 1.25 N/A
12.04 (11.19–12.84) 10.68 (10.08–11.08) 10.2 (CI N/A) 12.70 (10.24–13.86)a 14.41 (13.73–15.96) 161.09 (149.64–167.36) 157.57 (143.96–174.62) 157.40 (CI N/A) 3.11 (2.64–3.21) 3.26 (2.55–3.80) 5.60 (CI N/A)
TSH = thyroid-stimulating hormone; TT4 = total thyroxine; FT4 = free thyroxine; GA = gestational age; CI = confidence interval; N/A = not available. a 90% CI.
TPOAb-positive samples. For FT4, our RIs at both 15 and 18 week GA were narrower than the manufacturer's second trimester values; our intervals were also higher than the second trimester RI reported by Jarrige et al., especially for 15 week GA. Notably, the lower limits proposed by both the manufacturer (5.79 pmol/l) and Jarrige et al. (5.84 pmol/l) were below the 95% confidence interval of our derived lower limits for both time points (lower 95% CI = 7.30 pmol/l for 15 week GA, and 5.88 pmol/l for 18 week GA). There was closer agreement for the upper FT4 limit across the studies (Table 1). For TT4 and TSH, only non-pregnant RIs were available from the manufacturer, with no other second trimester RIs available in the literature for the Beckman Coulter Access® 2 assay. At 15 week GA, our RIs were relatively higher for TT4, and similar but slightly lower for TSH, than the corresponding non-pregnant RIs. At 18 week GA, the respective RIs for TT4 and TSH were very similar, aside from the upper limit of normal for TSH, which was lower in our study. Our TSH RIs were also assessed against the American Thyroid Association's recommended second trimester range of 0.2 to 3.0 mIU/l (suggested for laboratories without trimesterspecific RIs) [6], and were noted to be comparable. In this study, the RIs of TSH, TT4, and FT4 were established on the Beckman Coulter Access® 2 platform from a population of healthy, likely iodine-replete, predominantly Caucasian women in the early second trimester of pregnancy. Our RIs differed considerably from those reported for other assays (see Table 3 in Yan et al. [7] and Table 2 in Vila et al. [15] for compilations of pregnancy RIs for other assays described in the literature). Further, there were also discrepancies between our estimates as compared to those provided by the manufacturer, and to the RI determined by Jarrige et al. This highlights the variance in estimates of normality which may occur when RIs are determined from different patient populations — even when the same methodology is employed. There are numerous variables affecting FT4 concentrations which may be dissimilar between our population and those sampled in the manufacturer's study and in Jarrige et al.'s study. Specifically, as demonstrated by our findings, the difference in GA was an important factor which led to distinctly different estimates of the normal range, even between 15 and 18 weeks of gestation. The GA distribution within Jarrige et al.'s study was not provided in the abstract; therefore, we could not determine if the disagreement in FT4 limits was specifically attributable to differences in GA at the time of sample collection, or to genetic or demographic variations. This again illustrates the importance of developing trimester- (ideally GA-), method-, and population-specific RIs for all thyroid analytes. For TT4 and TSH, our derived RIs differed from the non-pregnant values listed by the manufacturer. These disparities were expected given the increased thyroid-binding globulin (TBG) concentration in pregnancy secondary to hyperestrogenemia, thereby giving rise to increased TT4 concentrations, and the cross-reactivity of circulating hCG with TSH, which leads to lower TSH concentrations in pregnant versus non-pregnant women [22].
The poor and/or lack of correlation we observed between maternal TSH and maternal FT4 concentrations was in agreement with the results of Williams et al. [23], who found a weak correlation between the two parameters at 10 week GA (r = − 0.243, P = 0.02) but not at 34 week GA. TSH's relatively weak correlation with FT4 during the late first trimester or early second trimester can be explained by hCG's dynamic nature (with concentrations peaking near the end of the first trimester), which distorts the normally robust inverse relationship between TSH and FT4 [22]. In conclusion, we have determined early second trimester RIs for TSH, TT4, and FT4 on the Beckman Coulter Access® 2 assay for a population of healthy, predominantly Caucasian females. Our findings reinforce the value of establishing GA- and population-specific RIs for thyroid analytes during pregnancy.
References [1] Davis LE, Lucas MJ, Hankins GD, Roark ML, Cunningham FG. Thyrotoxicosis complicating pregnancy. Am J Obstet Gynecol 1989;160:63–70. [2] Neale DM, Cootauco AC, Burrow G. Thyroid disease in pregnancy. Clin Perinatol 2007;34:543–57 [v-vi]. [3] Lazarus JH. Thyroid function in pregnancy. Br Med Bull 2011;97:137–48. [4] Baloch Z, Carayon P, Conte-Devolx B, et al. Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid 2003;13:3–126. [5] Abalovich M, Amino N, Barbour LA, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2007;92:S1–S47. [6] Stagnaro-Green A, Abalovich M, Alexander E, et al. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 2011;21:1081–125. [7] Yan YQ, Dong ZL, Dong L, et al. Trimester- and method-specific reference intervals for thyroid tests in pregnant Chinese women: methodology, euthyroid definition and iodine status can influence the setting of reference intervals. Clin Endocrinol (Oxf) 2011;74:262–9. [8] Medici M, de Rijke YB, Peeters RP, et al. Maternal early pregnancy and newborn thyroid hormone parameters: the Generation R study. J Clin Endocrinol Metab 2012;97:646–52. [9] Wyness SP, La'ulu SL, Roberts WL. First-trimester reference intervals for thyrotropin, free thyroxine, free thyroxine index and thyroxine for the Beckman Coulter UniCel(R) DxI 800 and Roche Modular Analytics E170 analyzers. Clin Chim Acta 2011;412:2346–8. [10] Gong Y, Hoffman BR. Free thyroxine reference interval in each trimester of pregnancy determined with the Roche Modular E-170 electrochemiluminescent immunoassay. Clin Biochem 2008;41:902–6. [11] Haddow JE, Knight GJ, Palomaki GE, McClain MR, Pulkkinen AJ. The reference range and within-person variability of thyroid stimulating hormone during the first and second trimesters of pregnancy. J Med Screen 2004;11:170–4. [12] Dhatt GS, Griffin G, Agarwal MM. Thyroid hormone reference intervals in an ambulatory Arab population on the Abbott Architect i2000 immunoassay analyzer. Clin Chim Acta 2006;364:226–9. [13] La'ulu SL, Roberts WL. Second-trimester reference intervals for thyroid tests: the role of ethnicity. Clin Chem 2007;53:1658–64. [14] Silvio R, Swapp KJ, La'ulu SL, Hansen-Suchy K, Roberts WL. Method specific secondtrimester reference intervals for thyroid-stimulating hormone and free thyroxine. Clin Biochem 2009;42:750–3. [15] Vila L, Serra-Prat M, Palomera E, et al. Reference values for thyroid function tests in pregnant women living in Catalonia, Spain. Thyroid 2010;20:221–5.
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Letter to the Editor
[16] Jarrige V, Meurisse H, D'Herbomez M. Reference intervals of maternal free thyroxine (FT4) at the second and third trimesters of pregnancy using the Beckman Coulter’s Access free T4 assay. Endocrine Abstracts, 11; 2006 P818. [17] Lee RH, Spencer CA, Mestman JH, et al. Free T4 immunoassays are flawed during pregnancy. Am J Obstet Gynecol 2009;200:260.e1–6. [18] Webster GM, Teschke K, Janssen PA. Recruitment of healthy first-trimester pregnant women: lessons from the Chemicals, Health & Pregnancy study (CHirP). Matern Child Health J 2012;16:430–8. [19] Surks MI, Sievert R. Drugs and thyroid function. N Engl J Med 1995;333:1688–94. [20] Barbesino G. Drugs affecting thyroid function. Thyroid 2010;20:763–70. [21] Statistics Canada. Iodine status of Canadians. 2009 to 2011. Accessed 18 July 2013, http://www.statcan.gc.ca/pub/82-625-x/2012001/article/11733-eng.htm. [22] Glinoer D. The regulation of thyroid function in pregnancy: pathways of endocrine adaptation from physiology to pathology. Endocr Rev 1997;18:404–33. [23] Williams FL, Watson J, Ogston SA, Visser TJ, Hume R, Willatts P. Maternal and umbilical cord levels of T4, FT4, TSH, TPOAb, and TgAb in term infants and neurodevelopmental outcome at 5.5 years. J Clin Endocrinol Metab 2013;98:829–38.
Sophia L. Wong Division of Medical Biochemistry, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada Corresponding author at: UBC Department of Pathology and Laboratory Medicine, 855 West 12th Avenue, Vancouver, British Columbia V5Z 1M9, Canada. E-mail address: [email protected].
Glenys M. Webster Child and Family Research Institute, Children's & Women's Health Centre of British Columbia, Vancouver, British Columbia, Canada Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada Scott Venners Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada Andre Mattman Division of Medical Biochemistry, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada Division of Medical Biochemistry, Department of Pathology and Laboratory Medicine, St. Paul’s Hospital, Vancouver, British Columbia, Canada 18 October 2013
Contents lists available at ScienceDirect
Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim
Letter to the Editor Second trimester thyroid-stimulating hormone, total and free thyroxine reference intervals for the Beckman Coulter Access® 2 platform
Dear Editor: Profound changes in thyroid hormones (THs) occur in the maternal body during pregnancy. These alterations pose a particular challenge for the interpretation of thyroid test results and the diagnosis of thyroid dysfunction in pregnant women. However, it remains vital to recognize maternal thyroid disease (whether hyper- or hypothyroidism), as failure to do so is associated with a litany of complications, including an increased likelihood of pre-eclampsia, placental abruption, spontaneous abortion, prematurity, impaired fetal cerebral development, low neonatal birthweight, and intrauterine growth restriction and death [1–3]. Reference intervals (RIs) found in the inserts of commercial assays are almost always derived from the general population and are not suitable for pregnant females. The U.S. National Academy of Clinical Biochemistry (NACB) [4] and the Endocrine Society [5] have advocated for the use of trimester-specific RIs, while the American Thyroid Association [6] has recommended both trimester- and method-dependent RIs to be developed for thyroid analytes during pregnancy. In addition, such factors as age, ethnicity (including ethnic-related characteristics — for example, dietary patterns), geographical location, and iodine status can not only affect the prevalence of thyroid disease, but also the establishment of TH reference ranges [7,8]. Although pregnancy TH RIs based on several platforms have been published [7,9–15], we are not aware of any reports which describe the RIs for the Beckman Coulter Access® 2 analyzer for the early second trimester, except for a brief abstract [16]. We are therefore publishing our observations from a RI study performed incidentally during an investigation which examined environmental chemical exposures and thyroid hormone physiology in pregnancy (GM Webster et al., manuscript submitted for publication). Specifically, we determined early second trimester RIs for thyroid-stimulating hormone (TSH), total thyroxine (TT4) and free thyroxine (FT4) via serum samples collected from healthy, likely iodine-replete, and predominantly Caucasian pregnant females. TT4 measurements were included because some believe pregnancy-adjusted TT4 (i.e. multiplication of the non-pregnancy TT4 RI by a factor of 1.5) to be a more reliable method of estimating FT4 status in pregnancy [17]. One hundred and fifty-two pregnant women (mean age of 34, range 25–43) living in the Greater Vancouver area (Canada) were enrolled between 2007 and 2008. Inclusion criteria were as previously described [18]; in brief, eligible participants were carrying a singleton pregnancy; had conceived without the use of assisted reproductive technology, fertility drugs, or hormones; had no prior diagnosis of thyroid disease; and were not taking antidepressants or other drugs known to affect TH concentrations [19,20]. In Canada, iodization of table salt has been made mandatory by law since 1949, and a recent national survey has shown an adequate median iodine concentration (1.06 μmol/l) in Canadians [21]. Iodine status in study subjects was monitored via a questionnaire inquiring about the intake of prenatal vitamins and their iodine content; 0009-8981/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.cca.2013.11.006
urinary iodine was not measured. This study was approved by the Institutional Review Board of the University of British Columbia and other participating research centers, and written consent was obtained from all participants. Two 20 ml samples of maternal blood were collected at 15 and 18 week gestational age (GA), respectively, and the separated serum was stored at −80 °C until analysis was performed. TSH, TT4, FT4, and thyroid peroxidase autoantibody (TPOAb) concentrations were measured on the Beckman Coulter Access® 2 assay (Mississauga, ON, Canada). Within- and between-day coefficients of variation (CVs) in our laboratory were within the manufacturer's specifications. Detection limits were 0.003 mIU/l for TSH, 6 nmol/l for TT4, 2.6 pmol/l for FT4, and 0.3 IU/ml for TPOAb. Patients with TPOAb above the upper reference limit (≥9 IU/ml, n = 14 [9.2%]) were excluded from RI determinations. In addition, one subject with a marked elevation in beta human chorionic gonadotropin (β-hCG) concentration and consequent thyrotoxicosis was also omitted from the study. An additional 4 subjects were excluded due to an incomplete data set (final n = 133). All statistical analyses were performed with SPSS (ver 19.0.0, SPSS Inc.). The central 95% RIs were determined non-parametrically for all thyroid analytes. Only maternal serum samples with normal TSH results (n = 124, as defined by a TSH within the central 95th percentile, for both 15 and 18 week GA collections) were used to establish the respective second trimester FT4 and TT4 RIs [9,13,14]. RI medians between 15 and 18 week GA were compared using the Wilcoxon signed-rank test. Pearson's correlation coefficient was used to study the degree of correlation between maternal TSH, TT4, and FT4 concentrations. A P-value of b0.05 was considered to be statistically significant. Demographics of the study participants (mean age of 34, range 25–43; 82% Caucasians) were previously published [18]. Table 1 lists the RIs for TSH, TT4 and FT4 derived in this study, the RIs provided by the manufacturer, and any second trimester TH RIs available in the literature for the Beckman Coulter Access® 2 assay. Note that the manufacturer provides both second trimester specific RIs and adult (non-pregnant) RIs for FT4, but only adult (non-pregnant) RIs for TT4 and TSH. Considering data from this study, the median maternal FT4 and TT4 concentrations were significantly higher at 15 week than at 18 week GA (FT4: 9.50 pmol/l vs. 8.45 pmol/l, P b 0.001; TT4: 125.19 nmol/l vs. 119.39 nmol/l, P b 0.001). In contrast, median maternal TSH concentrations were similar between the two time points (TSH: 1.28 mIU/l vs. 1.25 mIU/l, P = NS). A weak inverse correlation was noted between maternal FT4 and TSH at 18 week GA (r = − 0.226, P = 0.012), but not at 15 week GA (r = − 0.142, P = 0.116). An inverse correlation between maternal TT4 and TSH observed at 15 week GA did not reach statistical significance (r = − 0.167, P = 0.063); no correlation was observed at 18 week GA (r = 0.011, P = NS). As expected, all three thyroid analytes were highly correlated between 15 week and 18 week GA within women (FT4: r = 0.748, P b 0.001; TT4: r = 0.651, P b 0.001; TSH: r = 0.741, P b 0.001). Next, we compared the RIs derived in this study to the manufacturer's RIs, as well as to the FT4 RI determined by Jarrige et al. [16] (Table 1). Jarrige et al.'s second trimester data were derived from 139 pregnant females (iodine status unspecified), with exclusion of
Letter to the Editor
97
Table 1 Central 95% reference intervals for TSH, TT4, and FT4 in adult pregnant females measured on the Beckman Coulter Access® 2 platform.
FT4 (pmol/l) n = 124
TT4 (nmol/l) n = 124 TSH (mIU/l) n = 133
15 week GA (this study) 18 week GA (this study) Second trimester (Jarrige et al. [16]) Second trimester (manufacturer) Non-pregnant (manufacturer) 15 week GA (this study) 18 week GA (this study) Non-pregnant (manufacturer) 15 week GA (this study) 18 week GA (this study) Non-pregnant (manufacturer)
Lower limit (95% CI)
Median
Upper limit (95% CI)
7.61 (7.30–8.00) 6.80 (5.88–7.10) 5.84 (CI N/A) 5.79 (5.19–6.14)a 7.86 (7.00–8.57) 92.62 (78.98–104.36) 85.17 (66.69–94.56) 78.38 (CI N/A) 0.25 (0.04–0.55) 0.33 (0.17–0.51) 0.34 (CI N/A)
9.50 8.45 N/A N/A N/A 125.19 119.39 107.59 1.28 1.25 N/A
12.04 (11.19–12.84) 10.68 (10.08–11.08) 10.2 (CI N/A) 12.70 (10.24–13.86)a 14.41 (13.73–15.96) 161.09 (149.64–167.36) 157.57 (143.96–174.62) 157.40 (CI N/A) 3.11 (2.64–3.21) 3.26 (2.55–3.80) 5.60 (CI N/A)
TSH = thyroid-stimulating hormone; TT4 = total thyroxine; FT4 = free thyroxine; GA = gestational age; CI = confidence interval; N/A = not available. a 90% CI.
TPOAb-positive samples. For FT4, our RIs at both 15 and 18 week GA were narrower than the manufacturer's second trimester values; our intervals were also higher than the second trimester RI reported by Jarrige et al., especially for 15 week GA. Notably, the lower limits proposed by both the manufacturer (5.79 pmol/l) and Jarrige et al. (5.84 pmol/l) were below the 95% confidence interval of our derived lower limits for both time points (lower 95% CI = 7.30 pmol/l for 15 week GA, and 5.88 pmol/l for 18 week GA). There was closer agreement for the upper FT4 limit across the studies (Table 1). For TT4 and TSH, only non-pregnant RIs were available from the manufacturer, with no other second trimester RIs available in the literature for the Beckman Coulter Access® 2 assay. At 15 week GA, our RIs were relatively higher for TT4, and similar but slightly lower for TSH, than the corresponding non-pregnant RIs. At 18 week GA, the respective RIs for TT4 and TSH were very similar, aside from the upper limit of normal for TSH, which was lower in our study. Our TSH RIs were also assessed against the American Thyroid Association's recommended second trimester range of 0.2 to 3.0 mIU/l (suggested for laboratories without trimesterspecific RIs) [6], and were noted to be comparable. In this study, the RIs of TSH, TT4, and FT4 were established on the Beckman Coulter Access® 2 platform from a population of healthy, likely iodine-replete, predominantly Caucasian women in the early second trimester of pregnancy. Our RIs differed considerably from those reported for other assays (see Table 3 in Yan et al. [7] and Table 2 in Vila et al. [15] for compilations of pregnancy RIs for other assays described in the literature). Further, there were also discrepancies between our estimates as compared to those provided by the manufacturer, and to the RI determined by Jarrige et al. This highlights the variance in estimates of normality which may occur when RIs are determined from different patient populations — even when the same methodology is employed. There are numerous variables affecting FT4 concentrations which may be dissimilar between our population and those sampled in the manufacturer's study and in Jarrige et al.'s study. Specifically, as demonstrated by our findings, the difference in GA was an important factor which led to distinctly different estimates of the normal range, even between 15 and 18 weeks of gestation. The GA distribution within Jarrige et al.'s study was not provided in the abstract; therefore, we could not determine if the disagreement in FT4 limits was specifically attributable to differences in GA at the time of sample collection, or to genetic or demographic variations. This again illustrates the importance of developing trimester- (ideally GA-), method-, and population-specific RIs for all thyroid analytes. For TT4 and TSH, our derived RIs differed from the non-pregnant values listed by the manufacturer. These disparities were expected given the increased thyroid-binding globulin (TBG) concentration in pregnancy secondary to hyperestrogenemia, thereby giving rise to increased TT4 concentrations, and the cross-reactivity of circulating hCG with TSH, which leads to lower TSH concentrations in pregnant versus non-pregnant women [22].
The poor and/or lack of correlation we observed between maternal TSH and maternal FT4 concentrations was in agreement with the results of Williams et al. [23], who found a weak correlation between the two parameters at 10 week GA (r = − 0.243, P = 0.02) but not at 34 week GA. TSH's relatively weak correlation with FT4 during the late first trimester or early second trimester can be explained by hCG's dynamic nature (with concentrations peaking near the end of the first trimester), which distorts the normally robust inverse relationship between TSH and FT4 [22]. In conclusion, we have determined early second trimester RIs for TSH, TT4, and FT4 on the Beckman Coulter Access® 2 assay for a population of healthy, predominantly Caucasian females. Our findings reinforce the value of establishing GA- and population-specific RIs for thyroid analytes during pregnancy.
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Letter to the Editor
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Sophia L. Wong Division of Medical Biochemistry, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada Corresponding author at: UBC Department of Pathology and Laboratory Medicine, 855 West 12th Avenue, Vancouver, British Columbia V5Z 1M9, Canada. E-mail address: [email protected].
Glenys M. Webster Child and Family Research Institute, Children's & Women's Health Centre of British Columbia, Vancouver, British Columbia, Canada Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada Scott Venners Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada Andre Mattman Division of Medical Biochemistry, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada Division of Medical Biochemistry, Department of Pathology and Laboratory Medicine, St. Paul’s Hospital, Vancouver, British Columbia, Canada 18 October 2013
