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Table of Contents
Year : 2018  |  Volume : 22  |  Issue : 1  |  Page : 1-4

Trimester-specific thyroid-stimulating hormone: An Indian perspective

1 Department of Endocrinology, Bharti Hospital, Karnal, India
2 Department of Endocrinology, PGIMS, Rohtak, Haryana, India
3 Department of Thyroidology, INMAS, New Delhi, India
4 Department of Medicine, Regional Institute of Medical Sciences, Imphal, Manipur, India

Date of Web Publication8-Feb-2018

Correspondence Address:
Sanjay Kalra
Department of Endocrinology, Bharti Hospital, Karnal, Haryana
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijem.IJEM_107_17

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How to cite this article:
Kalra S, Agarwal S, Aggarwal R, Ranabir S. Trimester-specific thyroid-stimulating hormone: An Indian perspective. Indian J Endocr Metab 2018;22:1-4

How to cite this URL:
Kalra S, Agarwal S, Aggarwal R, Ranabir S. Trimester-specific thyroid-stimulating hormone: An Indian perspective. Indian J Endocr Metab [serial online] 2018 [cited 2019 Mar 26];22:1-4. Available from: http://www.ijem.in/text.asp?2018/22/1/1/206140

   Guidelines for Trimester-Specific Thyroid-Stimulating Hormone Top

Current guidelines on the management of thyroid disorders during pregnancy strongly recommend the establishment of population-based trimester-specific reference ranges for thyroid-stimulating hormone (TSH).[1] This is an important aspect of clinical endocrinology, as the reference range directly impacts clinical decision-making and institution of therapy. Population-based reference ranges are expected to be calculated based on data of healthy pregnant women, with no personal or family history of thyroid dysfunction, no visible or palpable goiter; history of thyroid disease, with optimal iodine intake; and negative thyroid peroxidase antibody status. In accordance with the International Federation of Clinical Chemistry,[2] reference intervals should extend from the 2.5th to 97.5th percentile.[3],[4] While standard investigations require a minimum of 120 measurements for the establishment of normal ranges, thyroid function tests need a minimum of 400 individual measurements for validation of healthy reference ranges.[5] This is due to the high interindividual variability and skewness of data.

   Variability of Thyroid-Stimulating Hormone Top

Factors to be considered in the interpretation of TSH in pregnancy are preanalytical factors such as gestational age, presence of thyroid antibodies, iodine status, multiple pregnancies, ethnicity, and time of collection of TSH sample. Serum human chorionic gonadotropin concentrations tend to be higher, and TSH concentrations tend to be lower in women with multiple pregnancies.[6]

Circadian TSH rhythm has been observed in pregnant women as well as in nonpregnant women, with this circadian variation persisting in the second and third trimesters. Thus, failure to standardize collection time may interfere with the results and interpretation of the tests.[7]

Different immunoassays result in different TSH values. In general, the 97.5th percentile of TSH for the first trimester is located in two groups: according to the Architect, Beckman, and Immulite platform, it is about 3.0 mIU/L, while according to Centaur and Roche, it is close to 4 mIU/L.[6]

   Indian Data Top

Over the past few years, Indian endocrinologists have worked hard to identify center-based or population-based trimester-specific data for TSH. Perhaps the first effort in this direction, by Kumar et al., from New Delhi, is available online only in abstract form.[8] The seminal effort of 2008 by Marwaha et al., from New Delhi, continues to enjoy sempiternal relevance.[9] This work has been expanded upon by Sekhri et al. from the same institute [10] and complemented by authors from Haryana, Maharashtra, and Manipur.[11],[12],[13] A well-conducted study from Bengal has also been published in 2014.[14] However, as this uses ELISA techniques to measure thyroid function tests, its relevance to modern thyroidology is debatable.

   Heterogeneity in Design and Results Top

In this editorial, we compare the data from the six relevant published studies on trimester-specific ranges for thyroid function tests [Table 1], [Table 2], [Table 3]. Broadly speaking, these studies have similar inclusion and exclusion criteria. Some are longitudinal in nature, whereas others are cross-sectional. Some studies rely on dietary history to assess iodine sufficiency, whereas others measure urinary iodide concentration to prove the same. Ultrasonography and thyroid antibodies screening are done by some, but not all authors for exclusion of nonhealthy participants. Most, authors mention the details of their kits, including sensitivity, coefficients of variation, nonpregnant reference ranges, and manufacturer identity. Some choose to report 5th and 95th percentile cutoffs, others prefer 2.5th and 97.5th percentiles, and yet others mention both. All mention mean values of thyroid function tests, whereas only four report median values. All but two measure free T3 and free T4 [Table 4]. This heterogeneity makes it difficult to compare these data sets. An eyeball analysis of the Indian data suggests that there is high heterogeneity between the various data sets. The lowest reference ranges are reported from Manipur and the highest from New Delhi. Rohtak and Nagpur reference ranges fall between those reported from Manipur and the national capital.
Table 1: Indian trimester-specific ranges for free triiodothyronine

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Table 2: Indian trimester-specific ranges for free thyroxine

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Table 3: Indian trimester-specific ranges for thyroid stimulating hormone

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Table 4: Research methodology

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   Need for Harmony Top

Reference ranges are of two types: health associated and decision based. The data discussed above are health associated, as it communicates thyroid function status of healthy Indian women. This does not necessarily translate into decision-making utility.[15] To do so, we need more robust data from all parts of the country, which can be analyzed together. We appreciate the opinion of Jebasingh et al., who highlight the multifaceted ethnic makeup of our country.[13] However, in a situation where limited funds are available, it makes sense to harmonize not only assays but also research methodology.[16],[17] This will help create a pan-India reference range for thyroid function tests not only in pregnancy [18] but also in other age groups.[15],[19],[20] These can be used to inform accurate and appropriate clinical decision-making throughout the country.

   Current Recommendations Top

Due to ethnic differences and geographical variations in populations, 2011 ATA and 2012 Endocrine Society guidelines recommended that the normal range of TSH should be determined locally for each population. The recommended upper TSH value in the first trimester in both the 2011 and the 2012 guidelines was 2.50 mU/L [21],[22] and 3.00 mU/L in second and third trimester. In the latest 2017 ATA thyroid and pregnancy guidelines, 19 studies published upper normal TSH limits (defined as the 97.5th percentile) ranging from 2.15 mU/L to 4.68 mU/L. A universal TSH cutoff distinguishing the upper range of normal from the lower range of abnormal does not exist.

The 2017 ATA thyroid and pregnancy guidelines recommend that an upper reference limit (URL) of 4.0 mU/L can be used if internal or transferable pregnancy-specific reference ranges of TSH are not available. However, a review of the 19 studies referenced in the 2017 ATA thyroid and pregnancy guidelines reveals that only 5 of 19 of the papers cited, reported an upper limit of normal ≥4.0 mU/L. Out of five largest studies cited (each including more than 5000 pregnant women), only one reported an upper limit of normal exceeding 3.5 mU/L. To ensure that most women with subclinical hypothyroidism are appropriately diagnosed, we conclude that recent 2017 recommendation of ATA of a revised URL for TSH of 4.0 mU/L is high and should instead be 3.0 mU/L in the first trimester and 3.5 in second and third trimester. These values should be used in India, till we are able to generate more nationally representative data for trimester-specific TSH values.

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Conflicts of interest

There are no conflicts of interest.

   References Top

Alexander EK, Pearce EN, Brent GA, Brown RS, Chen H, Dosiou C, et al. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid 2017;27:315-89.  Back to cited text no. 1
Solberg HE. The IFCC recommendation on estimation of reference intervals. The RefVal program. Clin Chem Lab Med 2004;42:710-4.  Back to cited text no. 2
Lazarus J, Brown RS, Daumerie C, Hubalewska-Dydejczyk A, Negro R, Vaidya B. 2014 European Thyroid Association guidelines for the management of subclinical hypothyroidism in pregnancy and in children. Eur Thyroid J 2014;3:76-94.  Back to cited text no. 3
De Groot L, Abalovich M, Alexander EK, Amino N, Barbour L, Cobin RH, et al. Management of thyroid dysfunction during pregnancy and postpartum: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2012;97:2543-65.  Back to cited text no. 4
Medici M, Korevaar TI, Visser WE, Visser TJ, Peeters RP. Thyroid function in pregnancy: What is normal? Clin Chem 2015;61:704-13.  Back to cited text no. 5
Maciel LM. Are TSH normal reference ranges adequate for pregnant women? Arch Endocrinol Metab 2016;60:303-6.  Back to cited text no. 6
Roti E, Bartalena L, Minelli R, Salvi M, Gardini E, Pistolesi A, et al. Circadian thyrotropin variations are preserved in normal pregnant women. Eur J Endocrinol 1995;133:71-4.  Back to cited text no. 7
Kumar A, Gupta N, Nath T, Sharma JB, Sharma S. Thyroid function tests in pregnancy. Indian J Med Sci 2003;57:252-8.  Back to cited text no. 8
[PUBMED]  [Full text]  
Marwaha RK, Chopra S, Gopalakrishnan S, Sharma B, Kanwar RS, Sastry A, et al. Establishment of reference range for thyroid hormones in normal pregnant Indian women. BJOG 2008;115:602-6.  Back to cited text no. 9
Sekhri T, Juhi JA, Wilfred R, Kanwar RS, Sethi J, Bhadra K, et al. Trimester specific reference intervals for thyroid function tests in normal Indian pregnant women. Indian J Endocrinol Metab 2016;20:101-7.  Back to cited text no. 10
Rajput R, Singh B, Goel V, Verma A, Seth S, Nanda S. Trimester-specific reference interval for thyroid hormones during pregnancy at a Tertiary Care Hospital in Haryana, India. Indian J Endocrinol Metab 2016;20:810-5.  Back to cited text no. 11
Mankar J, Sahasrabuddhe A, Pitale S. Trimester specific ranges for thyroid hormones in normal pregnancy. Thyroid Res Pract 2016;13:106.  Back to cited text no. 12
  [Full text]  
Jebasingh FK, Salam R, Meetei TL, Singh PT, Singh NN, Prasad L. Reference intervals in evaluation of maternal thyroid function of Manipuri women. Indian J Endocrinol Metab 2016;20:167-70.  Back to cited text no. 13
Maji R, Nath S, Lahiri S, Saha Das M, Bhattacharyya AR, Das HN. Establishment of trimester-specific reference intervals of serum TSH & fT4 in a pregnant Indian population at North Kolkata. Indian J Clin Biochem 2014;29:167-73.  Back to cited text no. 14
Boucai L, Hollowell JG, Surks MI. An approach for development of age-, gender-, and ethnicity-specific thyrotropin reference limits. Thyroid 2011;21:5-11.  Back to cited text no. 15
Koerbin G, Sikaris KA, Jones GR, Ryan J, Reed M, Tate J; AACB Committee for Common Reference Intervals. Evidence-based approach to harmonised reference intervals. Clin Chim Acta 2014;432:99-107.  Back to cited text no. 16
Aarsand AK, Sandberg S. How to achieve harmonisation of laboratory testing – The complete picture. Clin Chim Acta 2014;432:8-14.  Back to cited text no. 17
Glinoer D, Spencer CA. Serum TSH determinations in pregnancy: How, when and why? Nat Rev Endocrinol 2010;6:526-9.  Back to cited text no. 18
Clinical and Laboratory Standards Institute. Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline. 3rd ed. CLSI Document C28-A3. Wayne, PA: Clinical and Laboratory Standards Institute; 2008.  Back to cited text no. 19
Demers LM, Spencer CA. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid 2003;13:33-44.  Back to cited text no. 20
Stagnaro-Green A, Abalovich M, Alexander E, Azizi F, Mestman J, Negro R, 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.  Back to cited text no. 21
De Groot L, Abalovich M, Alexander EK, Amino N, Barbour L, Cobin RH, et al. Management of thyroid dysfunction during pregnancy and postpartum: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2012;97:2543-65.  Back to cited text no. 22


  [Table 1], [Table 2], [Table 3], [Table 4]


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