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Ethnic differences in first-trimester thyroid reference intervals.

To the Editor:

Thyroid disease thyroid disease Thyroid disorder Endocrinology Any benign or malignant condition that affects the structure or function of the thyroid gland. See Anaplastic carcinoma of thyroid, Chronic thyroiditis–Hashimoto's disease, Hyperthyroidism, Hypoparathyroidism,  is common in women of reproductive age, and the physiological changes that occur during pregnancy complicate the diagnosis of thyroid dysfunction. Trimester- and methodspecific reference intervals (RIs) [1] for thyroid function tests Thyroid Function Tests Definition

Thyroid function tests are blood tests used to evaluate how effectively the thyroid gland is working. These tests include the thyroid-stimulating hormone test (TSH), the thyroxine test (T4), the triiodothyronine test
 (TFTs) are necessary and should be determined with thyroid autoantibody-negative individuals (1). Ethnic differences in TFT (Thin Film Transistor) The term typically refers to active matrix screens on laptop computers. Active matrix LCD provides a sharper screen display and broader viewing angle than does passive matrix. See LCD and thin film.

TFT - Thin Film transistor
 results exist among nonpregnant individuals, but the data on ethnic differences in thyroid function during pregnancy are limited (2-5). We used the Abbott ARCHITECT [i2000.sub.SR] analyzer to determine RIs for TFTs by ethnic group for the first trimester of pregnancy.

Serum samples submitted between 10 and 13 weeks gestation were collected in the US from 540 Asians, 549 blacks, 601 Hispanics, and 878 whites (age, 15-46 years). Gestational ages were provided by the ordering physicians. Iodine status and medical histories were unknown, and only 1 sample was available from each individual. This study was approved by the University of Utah The University of Utah (also The U or the U of U or the UU), located in Salt Lake City, is the flagship public research university in the state of Utah, and one of 10 institutions that make up the Utah System of Higher Education.  Institutional Review Board. The numbers of thyroid autoantibody-negative individuals were 174, 579, 798, and 626 for gestational weeks 10, 11, 12, and 13, respectively. Samples from 129 self-reported healthy, non-pregnant adult individuals were obtained from 5 Asians, 2 blacks, 2 Hispanics, 114 whites, and 6 individuals of other ethnic backgrounds (63 females and 66 males, 18-62 years of age). Samples were thawed, mixed, centrifuged at 2095g for 10 min, and checked for clots before analysis. The following tests were performed on the ARCHITECT z2000SR: thyrotropin thyrotropin (thī'rätrō`pĭn) or thyroid-stimulating hormone (TSH), hormone released by the anterior pituitary gland that stimulates the thyroid gland to release thyroxine.  (TSH TSH thyroid-stimulating hormone; see thyrotropin.

thyroid-stimulating hormone

Thyroid-stimulating hormone (TSH) 
), free thyroxine ([FT.sub.4]), total thyroxine ([TT.sub.4]), free triiodothyronine triiodothyronine /tri·io·do·thy·ro·nine/ (tri?i-o?do-thi´ro-nen) one of the thyroid hormones, an organic iodine-containing compound liberated from thyroglobulin by hydrolysis. It has several times the biological activity of thyroxine.  ([FT.sub.3]), total triiodothyronine ([TT.sub.3]), thyroglobulin thyroglobulin /thy·ro·glob·u·lin/ (thi?ro-glob´u-lin) an iodine-containing glycoprotein of high molecular weight, occurring in the colloid of the follicles of the thyroid gland; the iodinated tyrosine moieties of thyroglobulin form the  autoantibodies, thyroid peroxidase autoantibodies, and T-uptake (measures the total binding capacity for thyroxine). The free thyroxine index free thyroxine index FT4I, T7 assay, T12 assay Endocrinology A lab value for T3 uptake combined with total T4; FTI is a clinical parameter measured by RIA, used to evaluate thyroid function, calculated by T4 x %T  (FTI FTI Free thyroxine index, see there ) and the thyroid hormone Thyroid hormone

Any of the chemical messengers produced by the thyroid gland, including thyrocalcitonin, a polypeptide, and thyroxine and triiodothyronine, which are iodinated thyronines. See Hormone, Thyrocalcitonin, Thyroid gland, Thyroxine
 binding ratio (THBR) were calculated per the package insert as [TT.sub.4]/ T-uptake and 1/T-uptake, respectively. The establishment of RIs and the analysis of ethnic differences were performed as previously described (4). We used autoantibody-negative samples for the nonparametric determination of RIs (central 95%) for both pregnant and nonpregnant individuals. Individuals with TSH values within the RI were used to determine the RIs for [FT.sub.4], FTI, [TT.sub.4], THBR, [FT.sub.3], and [TT.sub.3].

We used EP Evaluator Release 8 software (Data Innovations) to determine RIs. GraphPad Prism (version 5.03; GraphPad Software) was used for linear regression Linear regression

A statistical technique for fitting a straight line to a set of data points.
 analysis, the unpaired t-test, the [chi square chi square (kī),
n a nonparametric statistic used with discrete data in the form of frequency count (nominal data) or percentages or proportions that can be reduced to frequencies.
] test, and the Fisher exact test.

We observed numerous ethnic differences for the established first-trimester RI data (Table 1), in contrast to our findings for the second trimester (4). The RI for an ethnic group was considered significantly different ifit did not fall within the 95% CI of the reference limits for the combined group. For every analyte, both the lower and upper reference limits for at least 1 ethnic group were significantly different from those for all ethnic groups combined. It is difficult to compare the ethnic differences we observed with those established by other studies, because RIs can be method dependent and are affected by the gestational weeks included.

The use of thyroid autoantibody-negative individuals with a TSH value within the RI potentially narrows the RIs for other analytes. RIs for the other TFTs that were established by excluding only thyroid autoantibody-positive individuals were compared with RIs that were established with autoantibody-negative individuals with TSH results within the RI. No significant differences in lower reference limits were observed for any ethnic group; however, the upper reference limits for [FT.sub.4], [TT.sub.4], FTI, and [FT.sub.3] (19.4 pmol/L, 186 nmol/L, 125.6 nmol/L, 6.61 pmol/L, respectively) were significantly higher for black individuals when all antibody-negative individuals were included.

The lower reference limits for TSH were significantly lower in the first-trimester women compared with nonpregnant adults (Table 1). TSH suppression during pregnancy is associated with high concentrations of human chorionic gonadotropin human chorionic gonadotropin (HCG): see gonadotropic hormone.  [beta] subunit ([beta]-hCG) (1). All samples with TSH concentrations <0.35 mIU/L were tested for [beta]-hCG on the ARCHITECT [i2000.sub.SR]. Of the 282 samples tested, 26 individuals had [beta]-hCG concentrations >200 000 IU/L (7 Asian, 12 black, 2 Hispanic, and 5 white individuals). Exclusion of these individuals with very high [beta]-hCG concentrations did not significantly alter the lower reference limit for TSH.

RIs determined by gestational week for all groups combined showed an upward trend for [TT.sub.4] and a downward trend for FTI, in that the slopes were significantly different from zero by linear regression (P = 0.04 and 0.02, respectively). All other analytes showed no significant trends. RIs were also determined for nonpregnant adults and were compared with those for the combined group (Table 1). Comparisons of the nonpregnant group with the pregnant group showed that only the lower reference limit for [FT.sub.3] was not significantly different (Table 1).

Further analysis demonstrated that Asians have the highest prevalence of both thyroid autoantibodies and increased TSH concentrations. Blacks had the lowest prevalence of both. Similar results were observed in the second trimester (4). TSH concentrations were influenced by age for both whites and the combined group: A significantly higher percentage of individuals [greater than or equal to]30 years of age had an increased TSH (P < 0.003). For individuals with an increased TSH, 62% were positive for either thyroglobulin autoantibodies or thyroid peroxidase autoantibodies, and 23% were positive for both.

RIs for TFTs need to be specific by trimester trimester /tri·mes·ter/ (-mes´ter) a period of three months.

A period of three months.

The first third or 13 weeks of pregnancy.
, method, and possibly population. We observed significant differences among 4 ethnic groups in the first trimester. We recommend that studies evaluating TFTs report the ethnic make-up of their study populations.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the Disclosures of Potential Conflict of Interest form. Potential conflicts of interest:

Employment or Leadership: S.L. La'ulu, ARUP Laboratories.

Consultant or Advisory Role: W.L. Roberts, ARUP Laboratories. Stock Ownership: None declared. Honoraria: None declared. Research Funding: W.L. Roberts, Abbott Diagnostics and ARUP Laboratories. Expert Testimony Testimony about a scientific, technical, or professional issue given by a person qualified to testify because of familiarity with the subject or special training in the field. : None declared.

Role of Sponsor: The funding organizations played a direct role in the design of the study.

Acknowledgments: We gratefully acknowledge Joshua Hunsaker for sample collection and deidentification.


(1.) Mandel SJ, Spencer CA, Hollowell JG. Are detection and treatment of thyroid insufficiency in pregnancy feasible? Thyroid 2005;15:44-53.

(2.) Dhatt GS, Jayasundaram R, Wareth LA, Nagelkerke N, Jayasundaram K, Darwish EA, Lewis A. Thyrotrophin thyrotrophin /thy·ro·troph·in/ (-tro?fin) thyrotropin.


 and free thyroxine trimester-specific reference intervals in a mixed ethnic pregnant population in the United Arab Emirates United Arab Emirates, federation of sheikhdoms (2005 est. pop. 2,563,000), c.30,000 sq mi (77,700 sq km), SE Arabia, on the Persian Gulf and the Gulf of Oman. . Clin Chim Acta 2006;370:147-51.

(3.) Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, Braverman LE.Serum TSH, [T.sub.4], and thyroid antibodies thyroid antibodies See Antimyeloperoxidase antibody, Antithyroglobulin antibody, Antithyroid peroxidase antibody.  in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III NHANES III Third National Health & Nutrition Examination Survey Public health A population-based survey conducted by the National Center for Health Statistics, designed to assess the health and nutritional status of the noninstitutionalized Americans ). J Clin Endocrinol Metab 2002;87:489-99.

(4.) La'ulu SL, Roberts WL. Second-trimester reference intervals for thyroid tests: the role of ethnicity. Clin Chem 2007;53:1658-64.

(5.) Walker JA, Illions EH, Huddleston JF, Smallridge RC. Racial comparisons of thyroid function and autoimmunity during pregnancy and the postpartum period. Obstet Gynecol 2005;106:1365-71.

Sonia L. La'ulu [2] William L. Roberts [2,3]*

[1] Nonstandard non·stan·dard  
1. Varying from or not adhering to the standard: nonstandard lengths of board.

 abbreviations: RI, reference interval; TFT, thyroid function test thyroid function test,
n one of several tests to evaluate the function of the thyroid gland. These include protein-bound iodine, butanol-extractable iodine, radioactive iodine uptake, and radioactive iodine excretion.
; TSH, thyrotropin; [FT.sub.4], free thyroxine; [TT.sub.4], total thyroxine; [FT.sub.3], free triiodothyronine; [TT.sub.3], total triiodothyronine; T-uptake, measurement of total binding capacity of thyroxine-binding proteins for thyroid hormones; FTI, free thyroxine index; THBR, thyroid hormone binding ratio; [beta]-hCG, human chorionic gonadotropin [beta] subunit.

[2] ARUP Institute for Clinical and Experimental Pathology Salt Lake City, UT [3] Department of Pathology University of Utah Health Sciences Center Salt Lake City, UT

* Address correspondence to this author at: ARUP Laboratories 500 ChipetaWay Salt Lake City, UT 84108 Fax 801-584-5207 E-mail

Previously published online at DOI (Digital Object Identifier) A method of applying a persistent name to documents, publications and other resources on the Internet rather than using a URL, which can change over time. : 10.1373/clinchem.2010.161240
Table 1. Summary of first-trimester RI data.

                                  2.5th         95% CI         50th
                               Percentile       (2.5th      Percentile
Analyte/ethnic group    n     (lower limit)   percentile)    (median)

  Combined             2172    0.02            0.01-0.04      0.94
  Asian                 424    0.02            0.01-0.04      0.89
  Black                 506    0.01            0.00-0.03      0.82
  Hispanic              511    0.01            0.01-0.05      1.02
  White                 731    0.11 (a)        0.05-0.18      1.02
  Nonpregnant adult     129    0.59 (a)       <0.00-0.81      1.55
  Manufacturer1 (b)            0.35
[FT.sub.4], pmol/L
  Combined             2069   11.4             11.1-11.61    14.7
  Asian                 394   12.4 (a)         11.1-12.6     15.6
  Black                 482   11.1             10.7-11.7     14.6
  Hispanic              485   11.4             11.0-11.9     14.7
  White                 708   11.1             10.8-11.5     14.2
  Nonpregnant adult     123   10.7 (a)        <10.1-11.7     14.8
  Manufacturer (b)            9.0
[TT.sub.4], nmol/L
  Combined             2069   85                 83-86      124
  Asian                 394   85                 76-89      129
  Black                 482   85                 82-90      124
  Hispanic              485   87 (a)             83-94      128
  White                 708   83                 78-85      118
  Nonpregnant adult     122   68 (a)            <62-71      90
  Manufacturer (b)            63
  Combined             2069    0.57            0.56-0.57      0.72
  Asian                 394    0.58 (a)        0.55-0.59      0.73
  Black                 482    0.56            0.54-0.58      0.7
  Hispanic              485    0.55 (a)        0.53-0.56      0.69
  White                 708    0.58 (a)        0.57-0.59      0.75
  Nonpregnant adult     123    0.69 (a)        0.64-0.82      1.1
  Manufacturer (b)             0.69
FTI, nmol/L
  Combined             2069   69.0             66.7-70.2     90.1
  Asian                 394   71.3 (a)         56.8-75.1     96.4
  Black                 482   69.6             64.3-70.7     88.7
  Hispanic              485   67.9             65.3-70.8     88.6
  White                 708   67.7             64.7-70.0     89.3
  Nonpregnant adult     122   58.0 (a)         48.5-68.2     97.7
  Manufacturer (b)            65.2
[FT.sub.3], pmol/L
  Combined             2068    4.00            3.91-4.10      5.19
  Asian                 393    3.97            3.63-4.13      5.14
  Black                 482    4.25 (a)        3.93-4.37      5.21
  Hispanic              485    4.34 (a)        3.91-4.45      5.37
  White                 708    3.79 (a)        3.53-3.97      5.09
  Nonpregnant adult     123    3.97           <3.53-4.39      5.24
  Manufacturer (b)             2.63
[TT.sub.3], nmol/L
  Combined             2069    1.6             1.52-1.65    2.51
  Asian                 394    1.51 (a)        1.42-1.63    2.37
  Black                 482    1.72 (a)        1.62-1.79    2.6
  Hispanic              485    1.69 (a)        1.54-1.88    2.71
  White                 708    1.52            1.42-1.60    2.41
  Nonpregnant adult     123    1.36 (a)       <1.19-1.52    1.89
  Manufacturer (b)             0.89

                          97.5th         95% CI
                        Percentile       (97.5th
Analyte/ethnic group   (upper limit)   percentile)

  Combined               2.69           2.58-2.81
  Asian                  2.81           2.70-3.53
  Black                  2.40 (a)       2.10-2.85
  Hispanic               2.69           2.34-3.12
  White                  2.69           2.58-2.96
  Nonpregnant adult      3.27 (a)       2.87->3.76
  Manufacturer1 (b)      4.94
[FT.sub.4], pmol/L
  Combined              18.6            18.3-18.8
  Asian                 19.8 (a)        18.8-20.8
  Black                 18.6            17.9-19.2
  Hispanic              18.3            17.5-19.1
  White                 17.8 (a)        17.3-18.3
  Nonpregnant adult     17.7 (a)        16.9->19.4
  Manufacturer (b)      19.1
[TT.sub.4], nmol/L
  Combined             173               169-176
  Asian                178 (a)           172-189
  Black                180 (a)           171-184
  Hispanic             174               167-181
  White                163 (a)           158-168
  Nonpregnant adult    142 (a)           116->152
  Manufacturer (b)     151
  Combined               1.00           0.97-1.02
  Asian                  1.09 (a)       1.00-1.19
  Black                  0.94 (a)       0.91-1.00
  Hispanic               0.92 (a)       0.90-1.00
  White                  1.02           0.99-1.06
  Nonpregnant adult      1.41 (a)       1.35-1.49
  Manufacturer (b)       1.41
FTI, nmol/L
  Combined             115.3           114.2-117.7
  Asian                119.4 (a)       115.3-131.7
  Black                116.8           114.5-124.6
  Hispanic             115             110.0-119.7
  White                111.2 (a)       109.5-115.2
  Nonpregnant adult    126.5 (a)       120.4-130.4
  Manufacturer (b)     121.5
[FT.sub.3], pmol/L
  Combined               6.47           6.38-6.55
  Asian                  6.5            6.27-6.70
  Black                  6.5            6.24-6.59
  Hispanic               6.59 (a)       6.44-6.68
  White                  6.30 (a)       6.21-6.45
  Nonpregnant adult      6.72 (a)       6.41->7.01
  Manufacturer (b)       5.7
[TT.sub.3], nmol/L
  Combined               3.79           3.71-3.91
  Asian                  3.63 (a)       3.47-3.99
  Black                  3.82           3.62-4.05
  Hispanic               4.02 (a)       3.90-4.31
  White                  3.67 (a)       3.57-3.79
  Nonpregnant adult      3.05 (a)       2.71->4.20
  Manufacturer (b)       2.44

(a) Indicates a reference limit that is significantly different
because it did not fall within the 95% CI of the combined group.
(b) Reference limits for nonpregnant adults from the ARCHITECT
[i2000.sub.SR] package insert.
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Title Annotation:Letters to the Editor
Author:La'ulu, Sonia L.; Roberts, William L.
Publication:Clinical Chemistry
Article Type:Letter to the editor
Date:Jun 1, 2011
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