Region-specific reference intervals for TSH in pregnancy: time for changes in Brazil

José Augusto Sgarbi About the author

Over the past few years, the diagnosis of thyroid disorders during pregnancy has emerged as one of the major focuses of debate in clinical thyroidology. Whether we should or not universally screening all pregnant women in the first trimester of pregnancy (11. Vaidya B, Anthony S, Bilous M, Shields B, Drury J, Hutchison S, et al. Detection of thyroid dysfunction in early pregnancy: Universal screening or targeted high-risk case finding? J Clin Endocrinol Metab. 2007;92(1):203-7.) and what is the best pregnancy-trimester specific TSH reference range (22. Glinoer D, Spencer CA. Serum TSH determinations in pregnancy: how, when and why? Nat Rev Endocrinol. 2010;6(9):526-9.

3. Maciel LM. Are TSH normal reference ranges adequate for pregnant women? Arch Endocrinol Metab. 2016;60(4):303-6.
-44. Korevaar TIM. The upper limit for TSH during pregnancy: why we should stop using fixed limits of 2.5 or 3.0 mU/l. Thyroid Res. 2018;11:5.) has gained worldwide interest. Answers are necessary to guide clinicians and public health policies.

It is well-known that many complex physiological adaptations in the thyroid economy occur over a normal pregnancy (55. Maciel LMZ, Magalhães PKR. Tireóide e gravidez. Arq Bras Endocrinol Metab. 2008;52(7):1084-95.). In summary, the increased concentration of hepatic thyroid-binding globulin, of human chorionic gonadotropin, and the elevation of iodide renal clearance, stimulate the maternal thyroid machinery. All together, they lead to marked differences in TSH and thyroid hormone concentrations among pregnant and non-pregnant women, making interpretation of thyroid function tests difficult (66. Glinoer D. The regulation of thyroid function during normal pregnancy: importance of the iodine nutrition status. Best Pract Res Clinl Endocrinol Metab. 2004;18(2):133-52.).

Thyroid disorders in pregnancy are relatively frequent, and if not properly treated may be associated with a wide range of maternal and fetal adverse outcomes, most importantly miscarriage, premature delivery, preeclampsia, low fetal weight, reduced cognitive function in offspring and fetal death (77. Yasbeck CF, Sullivan SD. Thyroid disorders during pregnancy. Med Clin N Am. 2012;96(2):235-56.). Thus, despite controversies about the best strategy for screening thyroid dysfunctions in the first trimester of pregnancy, whether should be case-finding or universal screening approach (11. Vaidya B, Anthony S, Bilous M, Shields B, Drury J, Hutchison S, et al. Detection of thyroid dysfunction in early pregnancy: Universal screening or targeted high-risk case finding? J Clin Endocrinol Metab. 2007;92(1):203-7.), there is an understanding amongst medical societies guidelines that the diagnosis of gestational thyroid diseases should be based on pregnancy-method and region-specific reference ranges (88. 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(3):315-89.).

Many centers and countries (including Brazil) do not have own local population-specific TSH reference ranges available. In such cases, previous guidelines (99. 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(10):1081-125.) recommend using fixed TSH upper limits of 2.5 mU/l or 3.0 mU/l for the first, second or third trimesters, respectively. However, it has been speculated that these reference intervals could result in overdiagnosis, additional investigations and potentially unnecessary levothyroxine treatment for many patients (1010. Korevaar TIM, Medici M, Visser TJ, Peeters RP. Thyroid disease in pregnancy: new insights in diagnosis and clinical management. Nat Rev Endocrinol. 2017;13(10):610-22.). Thererfore, the most recent American Thyroid Association (ATA) guidelines (88. 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(3):315-89.) recommend pregnancy-specific and local-specific references ranges for TSH and, if not possible, to adopt a reference interval derived from a population with similar features and TSH assay. If none of this is feasible, the last recommended alternative is to reduce 0.5 mU/l from the reference values for non-pregnant women, which would result in approximately 4.0 mU/l in Brazil.

In fact, reference intervals for laboratory tests are crucial in patient's care by differentiating a healthy individual from the diseased. However, it is a complex task. Pregnancy- and local specific reference limits for TSH can be markedly affected by multiple prenalytical and analytical factors, such as age, gender, ethnicity, antithyroid antibodies, iodine status, TSH assays, and alterations on proteins and free fatty acids levels (1111. Maciel LM. Are TSH normal reference ranges adequate for pregnant women? Arch Endocrinol Metab. 2016;60(4):303-6.). In addition, the non-Gaussian distribution and a high inter individual variation of TSH levels in the normal population confers an extra challenge (1212. Vieira JG. Defining reference values for TSH: nearing perfection in a imperfect world. Arq Bras Endocrinol Metabol. 2010;54(7): 589-90.).

Subgrouping healthy reference intervals by age, gender and other characteristics, may help to improve the diagnostic accuracy (1313. Klee GG. Clinical interpretation of reference intervals and reference limits. A plea for assay harmonization. Clin Chem Lab Med. 2004;42(7):752-7.). The National Academy of Clinical Biochemistry (NACB) has proposed strict selection criteria to establish 95% confident healthy limits for TSH in a population, including absence of family history of thyroid disease, negativity for thyroid antibodies, no visible or palpable goiter, and absence of medications (1414. Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry J, et al. Guidelines Committee, National Academy of Clinical Biochemistry. Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid. 2003;13(1):3-126.).

In this issue of the Archives, Silva de Moraes and cols. report the results of an acclaimed study (1515. Silva de Moraes NAO, Almeida de Assis AS, Corcino CM, Saraiva DA, Louro Berbara TMB, Drummond Ventura CD, et al. Recent recommendations from ATA guidelines to define the upper reference range for serum TSH in the first trimester match reference ranges for pregnant women in Rio de Janeiro. Arch Endocrinol Metab. 2018;62(4):386-91.) aiming to establish a local population-specific reference intervals for serum TSH on a Brazilian subpopulation. Using a crosssection design, they included 270 participants aged 18 – 35 years old, with spontaneous pregnancy and gestational age up to 12 weeks, from four prenatal outpatient clinics in a coastal area of the state of Rio de Janeiro.

The study was challenging. Researchers innovated by creating groups with additional and even stricter selection criteria than those of the NCAB to establish TSH reference intervals. In a stepwise approach, they also excluded patients with thyroid ultrasound patterns of thyroiditis and those with iodine insufficiency defined according to the World Health Organization as median urinary iodine concentration < 150 μg/L. A reference group (RG) was composed of 225 participants who filled all NACB criteria. A selective reference group (SRG) was created excluding those with thyroiditis pattern on thyroid ultrasound (n = 170), and at a final step, a more selective reference group (MSRG, n = 130) was defined by excluding any pregnant women with urinary iodine concentration < 150 μg/L.

The TSH reference ranges corresponding to the 2.5th – 97.5th percentile in the first trimester in such studied subpopulation was 0.12 – 4.47 mU/l, 1.26 – 4.0 mU/l and 0.14 – 3.63 mU/l for the RG, SRG and MSRG groups, respectively. These results are in agreement with a previous study in a similar population I from Rio de Janeiro (1616. Felipe CL, Medina CC, Sieiro NL, Alexandru B, Mario V. Is an upper limit of 2.5 mUI/l for TSH appropriate for the first trimester of pregnancy among young TPO - women? Gynecol Endocrinol. 2010;26(1):54-7) and above the fixed upper limits of 2.5 mU/l recommended in the previous ATA guidelines (99. 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(10):1081-125.). These data support other recent studies showing that arbitrary cutoffs values for TSH instead of local-specific reference intervals may inappropriately increase the rate of overdiagnosis (1717. Amouzegar A, Ainy E, Khazan M, Mehran L, Hedayati M, Azizi F. Local versus international recommended TSH references in the assessment of thyroid function during pregnancy. Horm Metab Res. 2014;46(3):206-10.).

Despite some limitation such as the number of patients included being less than 400 (the number required to adequately define reference ranges for measurements with a skewed distribution such as TSH) (1818. Medici M, Korevaar TI, Visser WE, Visser TJ, Peeters RP. Thyroid function in pregnancy: what is normal? Clin Chem. 2015;61(5):704-13.), Silva de Moraes and cols. (1515. Silva de Moraes NAO, Almeida de Assis AS, Corcino CM, Saraiva DA, Louro Berbara TMB, Drummond Ventura CD, et al. Recent recommendations from ATA guidelines to define the upper reference range for serum TSH in the first trimester match reference ranges for pregnant women in Rio de Janeiro. Arch Endocrinol Metab. 2018;62(4):386-91.) offer a great contribution to the better understanding and diagnosing of thyroid dysfunction during pregnancy in Brazil.

However, these results cannot be generalized to the entire population. As a matter of fact, in a previous Brazilian study (1919. Rosario PW, Carvalho M, Calsolari MR. TSH reference values in the first trimester of gestation and correlation between maternal TSH and obstetric and neonatal outcomes: a prospective Brazilian study. Arch Endocrinol Metab. 2016;60(4):314-8.) conducted in the continental state of Minas Gerais with 660 pregnant women, the upper limit of serum TSH reference in the first trimester of gestation was 2.68 mU/l. Potential explanations for the divergence include differences in iodine consumption among the populations. A recent trial (2020. Saraiva DA, Morais NAOES, Martins Corcino C, Martins Benvenuto Louro Berbara T, Schtscherbyna A, Santos M, Botelho H et al. Iodine status of pregnant women from a coastal Brazilian state after the reduction in recommended iodine concentration in table salt according to governmental requirements. Nutrition. 2018;53:109-14.) with pregnant women from Rio de Janeiro showed that this population is iodine sufficient, while some other have reported an increased iodine deficiency prevalence in the state of Minas Gerais (2020. Saraiva DA, Morais NAOES, Martins Corcino C, Martins Benvenuto Louro Berbara T, Schtscherbyna A, Santos M, Botelho H et al. Iodine status of pregnant women from a coastal Brazilian state after the reduction in recommended iodine concentration in table salt according to governmental requirements. Nutrition. 2018;53:109-14.). In addition, in the study from Minas Gerais (1919. Rosario PW, Carvalho M, Calsolari MR. TSH reference values in the first trimester of gestation and correlation between maternal TSH and obstetric and neonatal outcomes: a prospective Brazilian study. Arch Endocrinol Metab. 2016;60(4):314-8.), thyroid ultrasound and thyroglobulin antibody were not performed to exclude thyroid autoimmunity, but these differences could justify a higher, but not a lower upper serum TSH reference limit.

Taken together, these data suggest that in such a diverse and continental-sized country as Brazil, each region should have its own specific reference values for TSH for each trimester of pregnancy, but this is still far away from reality (2121. Campos R de O, Barreto IS, Maia LR, Rebouças SC, Cerqueira TL, Oliveira CA, et al. Iodine nutritional status in Brazil: a meta-analysis of all studies performed in the country pinpoints to an insufficient evaluation and heterogeneity. Arch Endocrinol Metab. 2015;59(1):13-22.). In addition, these finding may have implications for interpretation of results by clinicians and highlight the need for changes in the current Brazilian guidelines, which still recommends the arbitrary value of 2.5 mU/l for the upper limit of TSH in the first trimester of gestation (2222. Sgarbi JA, Teixeira PF, Maciel LM, Mazeto GM, Vaisman M, Montenegro Junior RM, et al. Brazilian Society of Endocrinology and Metabolism. The Brazilian consensus for the clinical approach and treatment of subclinical hypothyroidism in adults: recommendations of the thyroid Department of the Brazilian Society of Endocrinology and Metabolism. Arq Bras Endocrinol Metabol. 2013;57(3):166-83.).

REFERENCES

  • 1
    Vaidya B, Anthony S, Bilous M, Shields B, Drury J, Hutchison S, et al. Detection of thyroid dysfunction in early pregnancy: Universal screening or targeted high-risk case finding? J Clin Endocrinol Metab. 2007;92(1):203-7.
  • 2
    Glinoer D, Spencer CA. Serum TSH determinations in pregnancy: how, when and why? Nat Rev Endocrinol. 2010;6(9):526-9.
  • 3
    Maciel LM. Are TSH normal reference ranges adequate for pregnant women? Arch Endocrinol Metab. 2016;60(4):303-6.
  • 4
    Korevaar TIM. The upper limit for TSH during pregnancy: why we should stop using fixed limits of 2.5 or 3.0 mU/l. Thyroid Res. 2018;11:5.
  • 5
    Maciel LMZ, Magalhães PKR. Tireóide e gravidez. Arq Bras Endocrinol Metab. 2008;52(7):1084-95.
  • 6
    Glinoer D. The regulation of thyroid function during normal pregnancy: importance of the iodine nutrition status. Best Pract Res Clinl Endocrinol Metab. 2004;18(2):133-52.
  • 7
    Yasbeck CF, Sullivan SD. Thyroid disorders during pregnancy. Med Clin N Am. 2012;96(2):235-56.
  • 8
    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(3):315-89.
  • 9
    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(10):1081-125.
  • 10
    Korevaar TIM, Medici M, Visser TJ, Peeters RP. Thyroid disease in pregnancy: new insights in diagnosis and clinical management. Nat Rev Endocrinol. 2017;13(10):610-22.
  • 11
    Maciel LM. Are TSH normal reference ranges adequate for pregnant women? Arch Endocrinol Metab. 2016;60(4):303-6.
  • 12
    Vieira JG. Defining reference values for TSH: nearing perfection in a imperfect world. Arq Bras Endocrinol Metabol. 2010;54(7): 589-90.
  • 13
    Klee GG. Clinical interpretation of reference intervals and reference limits. A plea for assay harmonization. Clin Chem Lab Med. 2004;42(7):752-7.
  • 14
    Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry J, et al. Guidelines Committee, National Academy of Clinical Biochemistry. Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid. 2003;13(1):3-126.
  • 15
    Silva de Moraes NAO, Almeida de Assis AS, Corcino CM, Saraiva DA, Louro Berbara TMB, Drummond Ventura CD, et al. Recent recommendations from ATA guidelines to define the upper reference range for serum TSH in the first trimester match reference ranges for pregnant women in Rio de Janeiro. Arch Endocrinol Metab. 2018;62(4):386-91.
  • 16
    Felipe CL, Medina CC, Sieiro NL, Alexandru B, Mario V. Is an upper limit of 2.5 mUI/l for TSH appropriate for the first trimester of pregnancy among young TPO - women? Gynecol Endocrinol. 2010;26(1):54-7
  • 17
    Amouzegar A, Ainy E, Khazan M, Mehran L, Hedayati M, Azizi F. Local versus international recommended TSH references in the assessment of thyroid function during pregnancy. Horm Metab Res. 2014;46(3):206-10.
  • 18
    Medici M, Korevaar TI, Visser WE, Visser TJ, Peeters RP. Thyroid function in pregnancy: what is normal? Clin Chem. 2015;61(5):704-13.
  • 19
    Rosario PW, Carvalho M, Calsolari MR. TSH reference values in the first trimester of gestation and correlation between maternal TSH and obstetric and neonatal outcomes: a prospective Brazilian study. Arch Endocrinol Metab. 2016;60(4):314-8.
  • 20
    Saraiva DA, Morais NAOES, Martins Corcino C, Martins Benvenuto Louro Berbara T, Schtscherbyna A, Santos M, Botelho H et al. Iodine status of pregnant women from a coastal Brazilian state after the reduction in recommended iodine concentration in table salt according to governmental requirements. Nutrition. 2018;53:109-14.
  • 21
    Campos R de O, Barreto IS, Maia LR, Rebouças SC, Cerqueira TL, Oliveira CA, et al. Iodine nutritional status in Brazil: a meta-analysis of all studies performed in the country pinpoints to an insufficient evaluation and heterogeneity. Arch Endocrinol Metab. 2015;59(1):13-22.
  • 22
    Sgarbi JA, Teixeira PF, Maciel LM, Mazeto GM, Vaisman M, Montenegro Junior RM, et al. Brazilian Society of Endocrinology and Metabolism. The Brazilian consensus for the clinical approach and treatment of subclinical hypothyroidism in adults: recommendations of the thyroid Department of the Brazilian Society of Endocrinology and Metabolism. Arq Bras Endocrinol Metabol. 2013;57(3):166-83.

Publication Dates

  • Publication in this collection
    Aug 2018

History

  • Received
    27 Aug 2018
  • Accepted
    27 Aug 2018
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