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Ethnic differences in first-trimester thyroid reference intervals.

To the Editor:

Thyroid disease 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 (TFTs) are necessary and should be determined with thyroid autoantibody-negative individuals (1). Ethnic differences in TFT 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 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 (TSH), free thyroxine ([FT.sub.4]), total thyroxine ([TT.sub.4]), free triiodothyronine ([FT.sub.3]), total triiodothyronine ([TT.sub.3]), thyroglobulin autoantibodies, thyroid peroxidase autoantibodies, and T-uptake (measures the total binding capacity for thyroxine). The free thyroxine index (FTI) and the thyroid hormone 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 analysis, the unpaired t-test, the [chi square] 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 [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, 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: 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 and free thyroxine trimester-specific reference intervals in a mixed ethnic pregnant population in the United Arab Emirates. 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 in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). 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 abbreviations: RI, reference interval; TFT, thyroid function test; 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: 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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