Home | About us | Editorial board | Search | Ahead of print | Current issue | Archives | Submit article | Instructions | Subscribe | Contacts | Advertise | Login 
 
Search Article 
  
Advanced search 
  Users Online: 1131 Home Print this page Email this page Small font sizeDefault font sizeIncrease font size  

 
Table of Contents
ORIGINAL ARTICLE
Year : 2018  |  Volume : 22  |  Issue : 1  |  Page : 7-12

A systematic review on normative values of trimester-specific thyroid function tests in Indian women


1 Department of Endocrinology, Mazumdar Shaw Medical Center, Narayana Health, Bengaluru, Karnataka, India
2 Department of Endocrinology, Sri Ramachandra Medical College, Chennai, Tamil Nadu, India
3 Department of Clinical Research, Mazumdar Shaw Medical Center, Narayana Health, Bengaluru, Karnataka, India

Date of Web Publication8-Feb-2018

Correspondence Address:
Subramanian Kannan
Department of Endocrinology, Diabetes and Metabolism, Mazumdar Shaw Medical Center, Narayana Health City, 258/A Bommasandra Industrial Area, Hosur Road, Bengaluru - 560 099, Karnataka
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijem.IJEM_211_17

Rights and Permissions
   Abstract 


Background: Small cross-sectional studies are published on the trimester-specific normal ranges of thyrotropin and thyroxine levels in Indian women from various parts of the country. Objective: We sought to review the published literature on thyroid function tests in normal pregnant Indian women to see if the pooled data from various studies can define normative data and hypothyroidism in pregnancy. Methods: We retrieved 56 studies from online databases with detailed search using multiple search terms. Unanimously eight studies were finalized. Results: Data of 2703 pregnant women (age 16–45 years; 966 were in the first trimester, 1072 in their second trimester, and 1037 women in their third trimester) were analyzed. All eight studies included singleton pregnancies from the northern and eastern part of India with seven studies being cross-sectional in nature. The exclusion criteria in all studies included those with historical/clinical evidence of thyroid dysfunction, those with family history of thyroid dysfunction, infertility and those with history of recurrent miscarriages (usually >3). Ultrasound evidence of thyroid disease, urinary iodine assessment, and thyroid antibodies were included as additional exclusion criteria in two, three, and four studies, respectively. None of the studies included the outcome of pregnancy as part of follow-up. As part of the pooled data analysis, the 5th–95th centile values of normal TSH extended from 0.09 to 6.65 IU/mL in the first trimester, 0.39–6.61 IU/mL in the second trimester, and 0.70–5.18 IU/mL in the third trimester. The FT4 levels (5th–95th centile values) extended from 8.24 to 25.74 pmol/L in the first trimester, 6.82–26.0 pmol/L, and 5.18–25.61 pmol/L in the third trimester. Conclusions: With due limitations imposed by the quality of the available studies, the current review suggests that upper normal limit of TSH values can extend up to 5–6 IU/mL in pregnancy.

Keywords: Indian pregnant women, thyroid function test, thyroid-stimulating hormone, trimester-specific


How to cite this article:
Kannan S, Mahadevan S, Sigamani A. A systematic review on normative values of trimester-specific thyroid function tests in Indian women. Indian J Endocr Metab 2018;22:7-12

How to cite this URL:
Kannan S, Mahadevan S, Sigamani A. A systematic review on normative values of trimester-specific thyroid function tests in Indian women. Indian J Endocr Metab [serial online] 2018 [cited 2018 Sep 18];22:7-12. Available from: http://www.ijem.in/text.asp?2018/22/1/7/224985




   Introduction Top


The major changes in thyroid function during pregnancy are an increase in serum thyroxine-binding globulin (TBG) concentrations and stimulation of the thyrotropin (TSH) receptor by human chorionic gonadotropin.[1] During pregnancy, serum TBG concentrations rise almost 2-fold (estrogen-related increased production and decreased clearance due to TBG sialylation).[2],[3] With due acknowledgement of the methodological issues with free T4 assay during pregnancy, some studies reported a decrease in free T4 during pregnancy, others reported no change or even an increase.[1],[4],[5] Because of the changes in thyroid physiology during pregnancy, the guidelines of the American Thyroid Association (ATA) recommended using trimester-specific reference ranges for TSH and method and trimester-specific reference ranges for serum free T4.[6] Commercial laboratories are supposed to provide these reference ranges, but many do not do this. In one of the largest population-based studies (over 13,000 pregnant women), the reference range (2.5–97.5th percentile) for TSH in the first trimester was 0.08–2.99 mU/L.[7],[8],[9],[10] This was the basis of the previous ATA recommendation of normal TSH values during pregnancy: first trimester 0.1–2.5, second trimester 0.2–3.0, and third trimester 0.3–3.0. However, more recent studies in pregnant women in Asia, India, and the Netherlands, have demonstrated only a modest reduction in the upper reference limit.[11],[12],[13],[14],[15] A study of 4800 pregnant women in China recently showed that the downward shift in the TSH reference range occurred at weeks 7–12, but the upper reference limit was only reduced from 5.31 to 4.34 mU/L.[12] Separate data from a recent prospective intervention trial in the United States support this finding.[16] Analysis of the TSH and free T4 “set-point” in pregnant women showed that reductions in free T4 were observed only when the serum TSH was >4.8 mU/L. In some cases, this was not statistically different from the nonpregnant state.[13],[15] There is limited availability of trimester-specific reference ranges calculated for most ethnic and racial populations with adequate iodine intake who are free of thyroid autoantibodies. The recent ATA guidelines [17] recommend using a TSH upper reference range of 4 mU/L when local assessments are not available. This reference limit should generally be applied beginning with the late first trimester, weeks 7–12, with a gradual return toward the nonpregnant range in the 2nd and 3rd trimesters. There are multiple small cross-sectional data from India on trimester-specific values of TSH from the northern and eastern part of India. We sought to pool this information to see if the pooled data from various studies can define normative data and thyroid dysfunction in pregnancy.


   Methods Top


A systematic review was performed to estimate (i) trimester-specific 5th–95th centile TSH values (ii) trimester-specific range of free T4 values in normal pregnant Indian women. This report follows a review protocol adhering to current standards for reporting of systematic reviews.[18]

Eligibility criteria

We chose to include studies involving thyroid function tests in normal Indian pregnant women. Normal singleton pregnancies were included in this study. The study had to have excluded those with any major comorbid illness including diabetes, hypertension, cardiac ailments, renal, or hepatic disorders and those on medications that can potentially affect thyroid function tests. Studies on women with recurrent miscarriages and infertility were excluded from the study. The chosen studies had to exclude women with history of thyroid disorder, medications for hypothyroid or hyperthyroidism, family history of thyroid dysfunction, and presence of goiter. Studies with prespecified cutoffs for diagnosis of hypothyroidism were excluded from the study.

Search strategy

The search strategy aimed to find both published and unpublished studies. A comprehensive search from each database's inception to March 2017 was conducted with no language restrictions. The databases included Ovid MEDLINE In-process and Other Nonindexed Citations, Ovid MEDLINE, CINNAHL, the Cochrane Controlled Trials Register, Ovid EMBASE, Web of Science, and Scopus. An initial limited search of these databases was undertaken followed by analysis of the text words contained in the title and abstract, and of the index terms used to describe article. A second search using all identified keywords and index terms was then undertaken across all included databases. Thirdly, the reference list of all identified reports and articles was searched for additional studies.

Keywords used for database search

The following key words were used primarily to search the database which include thyroid*, hyperthyr*, hypothyr*, tpo*, tsh, thyrotropin recep-tor antibod*, thyroid stimulating immunoglobulin*, thyrotropin-binding inhibit*, thyroxine, thyrotropin, thyroid microsomal antibodies, fertility, infertility, abortion*, miscarriag*, pregnan*, obstetric*, gestation * preterm deliver*, premature deliver*, intrauterine growth retardation*, fetal growth restriction*, intrauterine growth restriction* and child development*. MESH terms including thyroid gland, thyroid diseases immunoglobulins, thyroid-stimulating, thyrotropin, thyroxine, fertility, infertility, pregnancy pregnancy outcome, pregnancy complications, fetal growth retardation and child development were used for the search. The results were then filtered to only include those done in Indian women.

Study identification

Titles and subsequently abstracts of the articles were screened by two reviewers independently (SK and SM). Included articles for full-text screening were compared during a consensus meeting. In case of disagreement, a third reviewer (AS) was consulted for the decision on inclusion or exclusion for full-text evaluation. Articles that did not contribute to the answer of our research questions after full text evaluation were excluded. Only articles that described at least ten patients were eligible. Articles that did not report concentrations of TSH and/or free T4, and articles on thyroid antibodies in noneuthyroid populations were excluded. After consensus, the remaining articles were included for critical appraisal and assessed by two reviewers independently (SK and SM). Articles were judged on scientific quality according to the CONSORT [11],[19] and STROBE [12] statement.

Data extraction

Reviewers worked independently and in duplicate using a standardized web-based form collected the following information from each eligible study: (i) Year and Place where the study was conducted (ii) number of pregnant women studied in each trimester and their mean (standard deviation [SD]) age (iii) type of study (cross-sectional or longitudinal) and its exclusion criteria described in the study (iv) methodology of thyroid function tests done (v) mean, SD, median, range, 5th– 95th centile of TSH and T4 and/or free T4 in each study (vi) adequacy of Iodine intake assessed by urinary iodine studies (vii) outcome of pregnancy if mentioned.

Data analysis

All results were subject to double data entry. The mean, SD, median and range were calculated for continuous variables. Where statistical pooling was not possible the findings are presented in narrative form including tables and figures to aid in data presentation.


   Results Top


Search results

Out of 56 search results, nine studies were selected based on our objectives. Among the 9 studies, 8 studies were considered for review and data extraction. One was excluded in view of poor quality. Sevens studies are published manuscripts [13],[14],[15],[16],[20],[21],[22] while one study was poster at an endocrine conference (Choudhary et al.) [Table 1]. The detail of the study selection was described in [Figure 1].
Figure 1: Selection of studies

Click here to view
Table 1: Pooled data of selected studies

Click here to view


Study types

Among the eight selected studies seven were cross-sectional and one was longitudinal study.

Laboratory methods

TSH was measured by different assay methods which include electrochemiluminescence,[13],[15],[20] enzyme-linked immunosorbent assay,[14] enzyme immunoassay,[21] and chemiluminescence immunoassays.[16],[22]


   Results Top


We reviewed eight studies for trimester-specific TSH levels in normal Indian pregnant women. A total of 2703 pregnant woman were studied in the selected 8 studies out of which 966, 1072, and 1037 women were tested for TSH levels during first, second, and third, trimesters, respectively. Most of these studies were performed in the Northern and Eastern part of India. None of these studies followed up till the outcome of pregnancy. The exclusion criteria in all studies included those with historical/clinical evidence of thyroid dysfunction, those with family history of thyroid dysfunction, infertility and those with history of recurrent miscarriages (usually >3). Ultrasound evidence of thyroid disease, urinary iodine assessment, and thyroid antibodies were included as additional exclusion criteria in two, three, and four studies, respectively [Supplementary file 1]. While six studies mentioned the mean (SD) TSH and fT4 levels [Table 2], only four studies reported median TSH values with interquartile range [Table 3]. Out of the seven studies which reported fT4/T4 levels, six studies checked the free thyroxine (FT4) values while one reported total T4 levels. All the FT4 values are converted into pmol/L and presented in [Table 4]. As part of the pooled data analysis, the 5th–95th centile values of normal TSH levels were 0.09–6.65 IU/mL during the first trimester [Figure 2], 0.39–6.61 IU/mL during the second trimester [Figure 3], and 0.70–5.18 IU/mL during the third trimester [Figure 4]. The FT4 levels (5th–95th centile values) were 8.24–25.74 pmol/L in first trimester, 6.82–26.0 pmol/L and 5.18–25.61 pmol/L in the third trimester.
Figure 2: Extent of TSH (5th–95th centiles) during the first trimester across various studies

Click here to view
Figure 3: Extent of TSH (5th–95th centile) during the second trimester across various studies

Click here to view
Figure 4: Extent of TSH (5th–95th centiles) during the third trimester across various studies

Click here to view
Table 2: Trimester-specific mean thyroid-stimulating hormone values from selected studies

Click here to view
Table 3: Trimester-specific median thyroid-stimulating hormone values from selected studies

Click here to view
Table 4: Trimester-specific free thyroxine values

Click here to view



   Discussion Top


Although there is considerable heterogeneity in the exclusion criteria in the included studies, only the study from Marwaha et al. had a comprehensive exclusion criteria including clinical, sonographical and serological thyroid peroxidase antibodies and anti-Tg (TPO and anti-Tg).[13] However, it does come as a surprise when the range of TSH reaches up to 10 in some individuals in their study. One of the biggest limitation of the studies conducted have been lack of follow-up of the studied cohort to get details on their pregnancy outcomes. In one of the few outcome studies related to thyroid function, Nambiar et al. studied a cohort of 483 consecutive pregnant women in the first trimester and followed them till delivery.[23] Subjects were prespecified classified as TSH <2 μIU/mL and TPOAb negative (Group 1) TPOAb positive (Group 2), patients with TSH 2–4 μIU/mL and TPOAb negative (Group 3) TPOAb positive (Group 4) and TSH >4 μIU/mL (Group 5). Those with TPOAb positivity and TSH >4 μIU/mL were treated with thyroxine. A TSH >4 μIU/mL and TPOAb positivity were associated with increased rates of miscarriages. In another study of outcomes in patients with preeclampsia, mean (SD) TSH levels significantly different among those with normal blood pressure: TSH 2 (1.18), those with mild preeclampsia: 3.42 (1.61) mIU/L, and in those with severe preeclampsia 5.63 (2.37). Those with preeclampsia and higher TSH levels had higher risk of low birth weight.[24]

From the above discussion, it seems safe to diagnose thyroid dysfunction once TSH starts crossing 4.5–5 mIU/L which is the typical cutoff in nonpregnant state. It is important to understand that this is valid in those with proper exclusion criteria particularly those with negative antibodies. Hence, if a clinician decides not to treat a TSH levels between 3 and 5, it is important to make sure the anti-thyroid antibody (TPOAb and/or anti-Tg) is negative. More outcome-based studies are required to know the normative data on antibody positive and antibody negative patients. Studies from outhern and western part of India are also needed to see if there are any regional variations in thyroid functions.


   Conclusions Top


With due limitations imposed by the quality of the available studies, the current review suggests that upper normal limit of TSH values can extend up to 5–6 IU/mL in pregnancy and one can possibly use nonpregnant cutoffs for TSH to diagnose thyroid dysfunction in pregnancy provided appropriate exclusion criteria are met. These results also are closely in line with the recommendations from the recent ATA guidelines for diagnosis of hypothyroidism in pregnancy.

Acknowledgment

The authors would like to acknowledge Mr. Annapandian VM, Consultant (Academic) Narayana Hrudayalaya Foundations, Narayana Health, Bengaluru, Karnataka, India.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Glinoer D. The regulation of thyroid function in pregnancy: Pathways of endocrine adaptation from physiology to pathology. Endocr Rev 1997;18:404-33.  Back to cited text no. 1
[PUBMED]    
2.
Ain KB, Mori Y, Refetoff S. Reduced clearance rate of thyroxine-binding globulin (TBG) with increased sialylation: A mechanism for estrogen-induced elevation of serum TBG concentration. J Clin Endocrinol Metab 1987;65:689-96.  Back to cited text no. 2
[PUBMED]    
3.
Ballabio M, Poshychinda M, Ekins RP. Pregnancy-induced changes in thyroid function: Role of human chorionic gonadotropin as putative regulator of maternal thyroid. J Clin Endocrinol Metab 1991;73:824-31.  Back to cited text no. 3
[PUBMED]    
4.
Lee RH, Spencer CA, Mestman JH, Miller EA, Petrovic I, Braverman LE, et al. Free T4 immunoassays are flawed during pregnancy. Am J Obstet Gynecol 2009;200:260.e1-6.  Back to cited text no. 4
    
5.
Soldin OP, Tractenberg RE, Hollowell JG, Jonklaas J, Janicic N, Soldin SJ. Trimester-specific changes in maternal thyroid hormone, thyrotropin, and thyroglobulin concentrations during gestation: Trends and associations across trimesters in iodine sufficiency. Thyroid 2004;14:1084-90.  Back to cited text no. 5
[PUBMED]    
6.
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. 6
[PUBMED]    
7.
Dashe JS, Casey BM, Wells CE, McIntire DD, Byrd EW, Leveno KJ, et al. Thyroid-stimulating hormone in singleton and twin pregnancy: Importance of gestational age-specific reference ranges. Obstet Gynecol 2005;106:753-7.  Back to cited text no. 7
[PUBMED]    
8.
Stricker R, Echenard M, Eberhart R, Chevailler MC, Perez V, Quinn FA, et al. Evaluation of maternal thyroid function during pregnancy: The importance of using gestational age-specific reference intervals. Eur J Endocrinol 2007;157:509-14.  Back to cited text no. 8
[PUBMED]    
9.
Gilbert RM, Hadlow NC, Walsh JP, Fletcher SJ, Brown SJ, Stuckey BG, et al. Assessment of thyroid function during pregnancy:First-trimester (weeks 9-13) reference intervals derived from Western Australian women. Med J Aust 2008;189:250-3.  Back to cited text no. 9
[PUBMED]    
10.
Fitzpatrick DL, Russell MA. Diagnosis and management of thyroid disease in pregnancy. Obstet Gynecol Clin North Am 2010;37:173-93.  Back to cited text no. 10
[PUBMED]    
11.
Schulz KF, Altman DG, Moher D; CONSORT Group. CONSORT 2010 statement: Updated guidelines for reporting parallel group randomised trials. PLoS Med 2010;7:e1000251.  Back to cited text no. 11
[PUBMED]    
12.
von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP; STROBE Initiative. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: Guidelines for reporting observational studies. Lancet 2007;370:1453-7.  Back to cited text no. 12
    
13.
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. 13
[PUBMED]    
14.
Maji R, Nath S, Lahiri S, Saha Das M, Bhattacharyya AR, Das HN. Establishment of trimester-specific reference intervals of serum TSH and fT4 in a pregnant Indian population at North Kolkata. Indian J Clin Biochem 2014;29:167-73.  Back to cited text no. 14
[PUBMED]    
15.
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. 15
[PUBMED]    
16.
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. 16
  [Full text]  
17.
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. 17
[PUBMED]    
18.
Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. J Clin Epidemiol 2009;62:1006-12.  Back to cited text no. 18
[PUBMED]    
19.
Schulz KF, Altman DG, Moher D; CONSORT Group. CONSORT 2010 Statement: Updated guidelines for reporting parallel group randomised trials. J Clin Epidemiol 2010;63:834-40.  Back to cited text no. 19
[PUBMED]    
20.
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. 20
[PUBMED]    
21.
Deshwal VK, Yadav A, Gogoi J. Comparison of FT3, FT4 and TSH levels in pregnant women in Dehradun, India. J Acad Ind Res 2013;4:239-41.  Back to cited text no. 21
    
22.
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. 22
[PUBMED]    
23.
Nambiar V, Jagtap VS, Sarathi V, Lila AR, Kamalanathan S, Bandgar TR, et al. Prevalence and impact of thyroid disorders on maternal outcome in Asian-Indian pregnant women. J Thyroid Res 2011;2011:429097.  Back to cited text no. 23
[PUBMED]    
24.
Kharb S, Sardana D, Nanda S. Correlation of thyroid functions with severity and outcome of pregnancy. Ann Med Health Sci Res 2013;3:43-6.  Back to cited text no. 24
[PUBMED]  [Full text]  


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

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



 

Top
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

   Abstract Introduction Methods Results Results Discussion Conclusions Article Figures Article Tables
  In this article
 References

 Article Access Statistics
    Viewed727    
    Printed7    
    Emailed0    
    PDF Downloaded279    
    Comments [Add]    

Recommend this journal