Individualized Management of Subclinical Hypothyroidism

By Sidra Azim, MD and Christian Nasr, MD

Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services. Policy

Adverse effects of subclinical hypothyroidism, effects of therapy

Subclinical hypothyroidism has been associated with adverse metabolic, cardiovascular, neuromuscular, and cognitive effects and has been shown to have a detrimental impact on quality of life. However, studies of levothyroxine therapy in subclinical hypothyroidism have yielded mixed results.16 Subclinical hypothyroidism affects many biologic systems, and levothyroxine may have a role (Table 2).32–117

Adverse effects of subclinical hypothyroidism and the role for levothyroxine

Individualized management and shared decision making

The management of subclinical hypothyroidism should be individualized on the basis of extent of thyroid dysfunction, comorbid conditions, risk factors, and patient preference.118

Shared decision-making is key, weighing the risks and benefits of levothyroxine treatment and the patient’s goals. There is some evidence to support levothyroxine treatment in nonpregnant patients with overt hypothyroidism (TSH > 10 mIU/L) or in patients with TSH 5 to 10 mIU/L with symptoms or hyperlipidemia and in younger patients at risk of cardiovascular disease. 118

Table 3 describes various patient factors that should be considered during clinical evaluation and decisions about levothyroxine treatment in subclinical hypothyroidism. The risks of treatment should be kept in mind and explained to the patient. Levothyroxine has a narrow therapeutic range, causing a possibility of over-replacement, and a half-life of 7 days that can cause dosing errors to have longer effect.118,119

Factors favoring levothyroxine therapy in subclinical hypothyroidism

Adherence can be a challenge. The drug needs to be taken on an empty stomach because foods and supplements interfere with its absorption.118,120 In addition, the cost of medication, frequent biochemical monitoring, and possible need for titration can add to financial burden.

When choosing the dose, one should consider the degree of hypothyroidism or TSH elevation and the patient’s weight, and adjust the dose gently.

If the TSH is high-normal

It is proposed that a TSH range of 3 to 5 mIU/L overlaps with normal thyroid function in a great segment of the population, and at this level it is probably not associated with clinically significant consequences. For these reasons, levothyroxine therapy is not thought to be beneficial for those with TSH in this range.

Pollock et al121 found that, in patients with symptoms suggesting hypothyroidism and TSH values in the upper end of the normal range, there was no improvement in cognitive function or psychological well-being after 12 weeks of levothyroxine therapy.

However, due to the concern for possible adverse maternal and fetal outcomes and low IQ in children of pregnant patients with subclinical hypothyroidism, levothyroxine therapy is advised in those who are pregnant or planning pregnancy who have TSH levels higher than 2.5 mIU/L, especially if they have thyroid peroxidase antibody. Levothyroxine therapy is not recommended for pregnant patients with negative thyroid peroxidase antibody and TSH within the pregnancy-specific range or less than 4 mIU/L if the reference ranges are unavailable.

Keep in mind that, even at these TSH values, there is risk of progression to overt hypothyroidism, especially in the presence of thyroid peroxidase antibody, so patients in this group should be monitored closely.

If TSH is mildly elevated

The evidence to support levothyroxine therapy in patients with subclinical hypothyroidism with TSH levels less than 10 mIU/L remains inconclusive, and the decision to treat should be based on clinical judgment.2 The studies that have looked at the benefit of treating subclinical hypothyroidism in terms of cardiac, neuromuscular, cognitive, and neuropsychiatric outcomes have included patients with a wide range of TSH levels, and some of these studies were not stratified on the basis of degree of TSH elevation.

The risk that subclinical hypothyroidism will progress to overt hypothyroidism in patients with TSH higher than 8 mIU/L is high, and in 70% of these patients, the TSH level rises to more than 10 mIU/L within 4 years. Early treatment should be considered if the TSH is higher than 7 or 8 mIU/L.

If TSH is higher than 10 mIU/L

The strongest evidence in favor of treating subclinical hypothyroidism is in patients with TSH levels higher than 10 mIU/L.2 Thyroid dysfunction with this degree of TSH elevation has been associated with adverse cardiometabolic, neuromuscular, cognitive, and psychiatric effects as described above, and has been shown to improve with levothyroxine therapy.

Figure 2 outlines an algorithmic approach to subclinical hypothyroidism in nonpregnant patients as suggested by Peeters.122

References

Cooper DS, Biondi B. Subclinical thyroid disease. Lancet. 2012;379(9821):1142–1154. doi:10.1016/S0140-6736(11)60276-6
Fatourechi V. Subclinical hypothyroidism: an update for primary care physicians. Mayo Clin Proc. 2009;84(1):65–71. doi:10.4065/84.1.65
Laurberg P, Andersen S, Carle A, Karmisholt J, Knudsen N, Pedersen IB. The TSH upper reference limit: where are we at? Nat Rev Endocrinol. 2011;7(4):232–239. doi:10.1038/nrendo.2011.13
Wartofsky L, Dickey RA. The evidence for a narrower thyrotropin reference range is compelling. J Clin Endocrinol Metab. 2005;90(9):5483–5488. doi:10.1210/jc.2005-0455
Spencer CA, Hollowell JG, Kazarosyan M, Braverman LE. National Health and Nutrition Examination Survey III thyroid-stimulating hormone (TSH)-thyroperoxidase antibody relationships demonstrate that TSH upper reference limits may be skewed by occult thyroid dysfunction. J Clin Endocrinol Metab. 2007;92(11):4236–4240. doi:10.1210/jc.2007-0287
Fatourechi V, Klee GG, Grebe SK, et al. Effects of reducing the upper limit of normal TSH values. JAMA. 2003;290(24):3195–3196. doi:10.1001/jama.290.24.3195-b
Surks MI, Hollowell JG. Age-specifi c distribution of serum thyrotropin and antithyroid antibodies in the US population: implications for the prevalence of subclinical hypothyroidism. J Clin Endocrinol Metab. 2007;92(12):4575–4582. doi:10.1210/jc.2007-1499
Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T4,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(2):489–499. doi:10.1210/jcem.87.2.8182
Jonklaas J, Bianco AC, Bauer AJ, et al; American Thyroid Association Task Force on Thyroid Hormone Replacement. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement. Thyroid. 2014;24(12):1670–1751. doi:10.1089/thy.2014.0028
Hennessey JV, Espaillat R. Diagnosis and management of subclinical hypothyroidism in elderly adults: a review of the literature. J Am Geriatr Soc. 2015;63(8):1663–1673. doi:10.1111/jgs.13532
Razvi S, Shakoor A, Vanderpump M, Weaver JU, Pearce SH. The influence of age on the relationship between subclinical hypothyroidism and ischemic heart disease: a meta-analysis. J Clin Endocrinol Metab. 2008;93(8):2998–3007. doi:10.1210/jc.2008-0167
Hamilton TE, Davis S, Onstad L, Kopecky KJ. Thyrotropin levels in a population with no clinical, autoantibody, or ultrasonographic evidence of thyroid disease: implications for the diagnosis of subclinical hypothyroidism. J Clin Endocrinol Metab. 2008; 93(4):1224–1230. doi:10.1210/jc.2006-2300
Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med. 2000; 160(4):526–534. pmid:10695693
Teng W, Shan Z, Teng X, et al. Effect of iodine intake on thyroid diseases in China. N Engl J Med. 2006;354(26):2783–2793. doi:10.1056/NEJMoa054022
Negro R, Stagnaro-Green A. Diagnosis and management of subclinical hypothyroidism in pregnancy. BMJ. 2014; 349:g4929. doi:10.1136/bmj.g4929
Baumgartner C, Blum MR, Rodondi N. Subclinical hypothyroidism: summary of evidence in 2014. Swiss Med Wkly. 2014; 144:w14058.
doi:10.4414/smw.2014.14058
Stedman TL. Stedman’s Medical Dictionary. 28th ed. Baltimore, MD: Lippincott Williams and Wilkins; 2006.
Raza SA, Mahmood N. Subclinical hypothyroidism: controversies to consensus. Indian J Endocrinol Metab. 2013;17(suppl 3):S636–S642. doi:10.4103/2230-8210.123555
Huber G, Staub JJ, Meier C, et al. Prospective study of the spontaneous course of subclinical hypothyroidism: prognostic value of thyrotropin, thyroid reserve, and thyroid antibodies. J Clin Endocrinol Metab. 2002;87(7):3221–3226. doi:10.1210/jcem.87.7.8678
Diez JJ, Iglesias P, Burman KD. Spontaneous normalization of thyrotropin concentrations in patients with subclinical hypothyroidism. J Clin Endocrinol Metab. 2005;90(7):4124–4127. doi:10.1210/jc.2005-0375
Vanderpump MP, Tunbridge WM, French JM, et al. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham survey. Clin Endocrinol (Oxf). 1995;43(1):55–68. pmid:7641412
Li Y, Teng D, Shan Z, et al. Antithyroperoxidase and antithyroglobulin antibodies in a five-year follow-up survey of populations with different iodine intakes. J Clin Endocrinol Metab. 2008;93(5):1751–1757. doi:10.1210/jc.2007-2368
Hennessey JV, Klein I, Woeber KA, Cobin R, Garber JR. Aggressive case finding: a clinical strategy for the documentation of thyroid dysfunction. Ann Intern Med. 2015; 163(4):311–312. doi:10.7326/M15-0762
Rugge JB, Bougatsos C, Chou R. Screening and treatment of thyroid dysfunction: an evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2015;162(1):35–45. doi:10.7326/M14-1456
Ladenson PW, Singer PA, Ain KB, et al. American Thyroid Association guidelines for detection of thyroid dysfunction. Arch Intern Med. 2000;160(11):1573–1575. pmid:10847249
Garber JR, Cobin RH, Gharib H, et al; American Association of Clinical Endocrinologists and American Thyroid Association Taskforce on Hypothyroidism in Adults. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract. 2012;18(6):988–1028. doi:10.4158/EP12280.GL
Jorde R, Waterloo K, Storhaug H, Nyrnes A, Sundsfjord J, Jenssen TG. Neuropsychological function and symptoms in subjects with subclinical hypothyroidism and the effect of thyroxine treatment. J Clin Endocrinol Metab. 2006;91(1):145–153. doi:10.1210/jc.2005-1775
Joffe RT, Pearce EN, Hennessey JV, Ryan JJ, Stern RA. Subclinical hypothyroidism, mood, and cognition in older adults: a review. Int J Geriatr Psychiatry. 2013; 28(2):111–118. doi:10.1002/gps.3796
Cooper DS, Halpern R, Wood LC, Levin AA, Ridgway EC. L-thyroxine therapy in subclinical hypothyroidism. A double-blind, placebo controlled trial. Ann Intern Med. 1984; 101(1):18–24. pmid:6428290
Nystrom E, Caidahl K, Fager G, Wikkelso C, Lundberg PA, Lindstedt G. A double-blind cross-over 12-month study of L-thyroxine treatment of women with ‘subclinical’ hypothyroidism. Clin Endocrinol (Oxf). 1988;29(1):63–75. pmid:3073880
Monzani F, Del Guerra P, Caraccio N, et al. Subclinical hypothyroidism: neurobehavioral features and beneficial effect of L-thyroxine treatment. Clin Investig. 1993;71(5):367–371. pmid:8508006
Biondi B. Thyroid and obesity: an intriguing relationship. J Clin Endocrinol Metab. 2010;95(8):3614–3617. doi:10.1210/jc.2010-1245
Erdogan M, Canataroglu A, Ganidagli S, Kulaksizoglu M. Metabolic syndrome prevalence in subclinic and overt hypothyroid patients and the relation among metabolic syndrome parameters. J Endocrinol Invest. 2011;34(7):488–492. doi:10.3275/7202
Javed Z, Sathyapalan T. Levothyroxine treatment of mild subclinical hypothyroidism: a review of potential risks and benefits. Ther Adv Endocrinol Metab. 2016;7(1):12–23. doi:10.1177/2042018815616543
Pearce SH, Brabant G, Duntas LH, et al. 2013 ETA guideline: management of subclinical hypothyroidism. Eur Thyroid J. 2013;2(4):215–228. doi:10.1159/000356507
Wang C. The relationship between type 2 diabetes mellitus and related thyroid diseases. J Diabetes Res. 2013;2013:390534. doi:10.1155/2013/390534
Razvi S, Weaver JU, Vanderpump MP, Pearce SH. The incidence of ischemic heart disease and mortality in people with subclinical hypothyroidism: reanalysis of the Whickham survey cohort. J Clin Endocrinol Metab. 2010;95(4):1734–1740. doi:10.1210/jc.2009-1749
Bindels AJ, Westendorp RG, Frolich M, Seidell JC, Blokstra A, Smelt AH. The prevalence of subclinical hypothyroidism at different total plasma cholesterol levels in middle aged men and women: a need for case-finding? Clin Endocrinol (Oxf). 1999;50(2):217–220. pmid:10396365
Pearce EN. Hypothyroidism and dyslipidemia: modern concepts and approaches. Curr Cardiol Rep. 2004;6(6):451–456. pmid:15485607
Pearce EN. Update in lipid alterations in subclinical hypothyroidism. J Clin Endocrinol Metab. 2012; 97(2):326–333. doi:10.1210/jc.2011-2532
Rizos CV, Elisaf MS, Liberopoulos EN. Effects of thyroid dysfunction on lipid profile. Open Cardiovasc Med J. 2011;5:76–84. doi:10.2174/1874192401105010076
Peppa M, Betsi G, Dimitriadis G. Lipid abnormalities and cardiometabolic risk in patients with overt and subclinical thyroid disease. J Lipids. 2011; 2011:575840. doi:10.1155/2011/575840
Asvold BO, Vatten LJ, Nilsen TI, Bjoro T. The association between TSH within the reference range and serum lipid concentrations in a population-based study: the HUNT study. Eur J Endocrinol. 2007;156(2):181–186. doi:10.1530/eje.1.02333
Danese MD, Ladenson PW, Meinert CL, Powe NR. Clinical review 115: effect of thyroxine therapy on serum lipoproteins in patients with mild thyroid failure: a quantitative review of the literature. J Clin Endocrinol Metab. 2000;85(9):2993–3001. doi:10.1210/jcem.85.9.6841
Razvi S, Ingoe L, Keeka G, Oates C, McMillan C, Weaver JU. The beneficial effect of L-thyroxine on cardiovascular risk factors, endothelial function, and quality of life in subclinical hypothyroidism: randomized, crossover trial. J Clin Endocrinol Metab. 2007; 92(5):1715–1723. doi:10.1210/jc.2006-1869
Abreu IM, Lau E, de Sousa Pinto B, Carvalho D. Subclinical hypothyroidism: to treat or not to treat, that is the question! A systematic review with meta-analysis on lipid profile. Endocr Connect. 2017; 6(3):188–199. doi:10.1530/EC-17-0028
Robison CD, Bair TL, Horne BD, et al. Hypothyroidism as a risk factor for statin intolerance. J Clin Lipidol. 2014;8(4):401–407. doi:10.1016/j.jacl.2014.05.005
Hak AE, Pols HA, Visser TJ, Drexhage HA, Hofman A, Witteman JC. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam study. Ann Intern Med. 2000;132(4):270–278. pmid:10681281
Boekholdt SM, Titan SM, Wiersinga WM, et al. Initial thyroid status and cardiovascular risk factors: the EPIC-Norfolk prospective population study. Clin Endocrinol (Oxf). 2010; 72(3):404–410. doi:10.1111/j.1365-2265.2009.03640.x
Andersen MN, Olsen AM, Madsen JC, et al. Levothyroxine substitution in patients with subclinical hypothyroidism and the risk of myocardial infarction and mortality. PLoS One. 2015; 10(6):e0129793. doi:10.1371/journal.pone.0129793
Biondi B. Cardiovascular effects of mild hypothyroidism. Thyroid. 2007;17(7):625–630. doi:10.1089/thy.2007.0158
Brenta G, Mutti LA, Schnitman M, Fretes O, Perrone A, Matute ML. Assessment of left ventricular diastolic function by radionuclide ventriculography at rest and exercise in subclinical hypothyroidism, and its response to L-thyroxine therapy. Am J Cardiol. 2003;91(11):1327–1330. pmid:12767425
Taddei S, Caraccio N, Virdis A, et al. Impaired endothelium-dependent vasodilatation in subclinical hypothyroidism: beneficial effect of levothyroxine therapy. J Clin Endocrinol Metab. 2003;88(8):3731–3737. doi:10.1210/jc.2003-030039
Gao N, Zhang W, Zhang YZ, Yang Q, Chen SH. Carotid intima-media thickness in patients with subclinical hypothyroidism: a meta-analysis. Atherosclerosis. 2013;227(1):18–25. doi:10.1016/j.atherosclerosis.2012.10.070
Biondi B, Cooper DS. The clinical significance of subclinical thyroid dysfunction. Endocr Rev. 2008; 29(1):76–131. doi:10.1210/er.2006-0043
Chaker L, Baumgartner C, den Elzen WP, et al; Thyroid Studies Collaboration. Subclinical hypothyroidism and the risk of stroke events and fatal stroke: an individual participant data analysis. J Clin Endocrinol Metab. 2015;100(6):2181–2191. doi:10.1210/jc.2015-1438
Monzani F, Di Bello V, Caraccio N, et al. Effect of levothyroxine on cardiac function and structure in subclinical hypothyroidism: a double blind, placebo-controlled study. J Clin Endocrinol Metab. 2001;86(3):1110–1115. doi:10.1210/jcem.86.3.7291
Parle JV, Maisonneuve P, Sheppard MC, Boyle P, Franklyn JA. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study. Lancet. 2001;358(9285):861-865. doi:10.1016/S0140-6736(01)06067-6
Razvi S, Weaver JU, Butler TJ, Pearce SH. Levothyroxine treatment of subclinical hypothyroidism, fatal and nonfatal cardiovascular events, and mortality. Arch Intern Med. 2012;172(10):811–817.
doi:10.1001/archinternmed.2012.1159
Pasqualetti G, Tognini S, Polini A, Caraccio N, Monzani F. Is subclinical hypothyroidism a cardiovascular risk factor in the elderly? J Clin Endocrinol Metab. 2013;98(6):2256–2266. doi:10.1210/jc.2012-3818
Mooijaart SP, IEMO 80-plus Thyroid Trial Collaboration. Subclinical thyroid disorders. Lancet. 2012; 380(9839):335. doi:10.1016/S0140-6736(12)61241-0
Rodondi N, Bauer DC. Subclinical hypothyroidism and cardiovascular risk: how to end the controversy. J Clin Endocrinol Metab. 2013;98(6):2267–2269. doi:10.1210/jc.2013-1875
Rodondi N, Newman AB, Vittinghoff E, et al. Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death. Arch Intern Med. 2005;165(21):2460–2466. doi:10.1001/archinte.165.21.2460
Rodondi N, Bauer DC, Cappola AR, et al. Subclinical thyroid dysfunction, cardiac function, and the risk of heart failure: the cardiovascular health study. J Am Coll Cardiol. 2008;52(14):1152–1159. doi:10.1016/j.jacc.2008.07.009
Haggerty JJ Jr, Garbutt JC, Evans DL, et al. Subclinical hypothyroidism: a review of neuropsychiatric aspects. Int J Psychiatry Med. 1990;20(2):193–208. doi:10.2190/ADLY-1UU0-1A8L-HPXY
Baldini IM, Vita A, Mauri MC, et al. Psychopathological and cognitive features in subclinical hypothyroidism. Prog Neuropsychopharmacol Biol Psychiatry. 1997;21(6):925–935. pmid:9380789
del Ser Quijano T, Delgado C, Martinez Espinosa S, Vazquez C. Cognitive deficiency in mild hypothyroidism. Neurologia. 2000;15(5):193–198. Spanish. pmid:10850118
Correia N, Mullally S, Cooke G, et al. Evidence for a specific defect in hippocampal memory in overt and subclinical hypothyroidism. J Clin Endocrinol Metab. 2009;94(10):3789–3797. doi:10.1210/jc.2008-2702
Aghili R, Khamseh ME, Malek M, et al. Changes of subtests of Wechsler memory scale and cognitive function in subjects with subclinical hypothyroidism following treatment with levothyroxine. Arch Med Sci. 2012;8(6):1096–1101. doi:10.5114/aoms.2012.32423
Pasqualetti G, Pagano G, Rengo G, Ferrara N, Monzani F. Subclinical hypothyroidism and cognitive impairment: systematic review and meta-analysis. J Clin Endocrinol Metab. 2015;100(11):4240–4248.
doi:10.1210/jc.2015-2046
Christ-Crain M, Meier C, Huber PR, Staub J, Muller B. Effect of L-thyroxine replacement therapy on surrogate markers of skeletal and cardiac function in subclinical hypothyroidism. Endocrinologist. 2004;14(3):161–166. doi:10.1097/01.ten.0000127932.31710.4f
Brennan MD, Powell C, Kaufman KR, Sun PC, Bahn RS, Nair KS. The impact of overt and subclinical hyperthyroidism on skeletal muscle. Thyroid. 2006; 16(4):375–380. doi:10.1089/thy.2006.16.375
Reuters VS, Teixeira Pde F, Vigario PS, et al. Functional capacity and muscular abnormalities in subclinical hypothyroidism. Am J Med Sci. 2009; 338(4):259–263. doi:10.1097/MAJ.0b013e3181af7c7c
Mainenti MR, Vigario PS, Teixeira PF, Maia MD, Oliveira FP, Vaisman M. Effect of levothyroxine replacement on exercise performance in subclinical hypothyroidism. J Endocrinol Invest. 2009;32(5):470–473. doi:10.3275/6106
Lankhaar JA, de Vries WR, Jansen JA, Zelissen PM, Backx FJ. Impact of overt and subclinical hypothyroidism on exercise tolerance: a systematic review. Res Q Exerc Sport. 2014; 85(3):365–389. doi:10.1080/02701367.2014.930405
Lee JS, Buzkova P, Fink HA, et al. Subclinical thyroid dysfunction and incident hip fracture in older adults. Arch Intern Med. 2010;170(21):1876–1883. doi:10.1001/archinternmed.2010.424
Svare A, Nilsen TI, Asvold BO, et al. Does thyroid function influence fracture risk? Prospective data from the HUNT2 study, Norway. Eur J Endocrinol. 2013; 169(6):845–852. doi:10.1530/EJE-13-0546
Di Mase R, Cerbone M, Improda N, et al. Bone health in children with long-term idiopathic subclinical hypothyroidism. Ital J Pediatr. 2012;38:56. doi:10.1186/1824-7288-38-56
Boelaert K. The association between serum TSH concentration and thyroid cancer. Endocr Relat Cancer. 2009;16(4):1065–1072. doi:10.1677/ERC-09-0150
Haymart MR, Glinberg SL, Liu J, Sippel RS, Jaume JC, Chen H. Higher serum TSH in thyroid cancer patients occurs independent of age and correlates with extra thyroidal extension. Clin Endocrinol (Oxf). 2009;71(3):434–439. doi:10.1111/j.1365-2265.2008.03489.x
Fiore E, Vitti P. Serum TSH and risk of papillary thyroid cancer in nodular thyroid disease. J Clin Endocrinol Metab. 2012; 97(4):1134–1145. doi:10.1210/jc.2011-2735
Fiore E, Rago T, Provenzale MA, et al. L-thyroxine-treated patients with nodular goiter have lower serum TSH and lower frequency of papillary thyroid cancer: results of a cross-sectional study on 27,914 patients. Endocr Relat Cancer. 2010;17(1):231–239. doi:10.1677/ERC-09-0251
Hercbergs AH, Ashur-Fabian O, Garfield D. Thyroid hormones and cancer: clinical studies of hypothyroidism in oncology. Curr Opin Endocrinol Diabetes Obes. 2010; 17(5):432–436. doi:10.1097/MED.0b013e32833d9710
Thvilum M, Brandt F, Brix TH, Hegedus L. A review of the evidence for and against increased mortality in hypothyroidism. Nat Rev Endocrinol. 2012;8(7):417–424. doi:10.1038/nrendo.2012.29
Stott DJ, Rodondi N, Kearney PM, et al; TRUST Study Group. Thyroid hormone therapy for older adults with subclinical hypothyroidism. N Engl J Med. 2017;376(26):2534–2544. doi:10.1056/NEJMoa1603825
Practice Committee of the American Society for Reproductive Medicine. Subclinical hypothyroidism in the infertile female population: a guideline. Fertil Steril. 2015; 104(3):545–753. doi:10.1016/j.fertnstert.2015.05.028
Stagnaro-Green A, Abalovich M, Alexander E, et al; American Thyroid Association Taskforce on Thyroid Disease During Pregnancy and Postpartum. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid. 2011; 21(10):1081–1125.doi:10.1089/thy.2011.0087
Goldsmith RE, Sturgis SH, Lerman J, Stanbury JB. The menstrual pattern in thyroid disease. J Clin Endocrinol Metab. 1952;12(7):846-855. doi:10.1210/jcem-12-7-846
Plowden TC, Schisterman EF, Sjaarda LA, et al. Subclinical hypothyroidism and thyroid autoimmunity are not associated with fecundity, pregnancy loss, or live birth. J Clin Endocrinol Metab. 2016;101(6):2358–2365. doi:10.1210/jc.2016-1049
Alexander EK, Pearce EN, Brent GA, 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):315–389. doi:10.1089/thy.2016.0457
Negro R, Formoso G, Mangieri T, Pezzarossa A, Dazzi D, Hassan H. Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: effects on obstetrical complications. J Clin Endocrinol Metab. 2006; 91(7):2587–2591. doi:10.1210/jc.2005-1603
Panesar NS, Li CY, Rogers MS. Reference intervals for thyroid hormones in pregnant Chinese women. Ann Clin Biochem. 2001;38(pt 4):329–332. doi:10.1258/0004563011900830
Lepoutre T, Debieve F, Gruson D, Daumerie C. Reduction of miscarriages through universal screening and treatment of thyroid autoimmune diseases. Gynecol Obstet Invest. 2012; 74(4):265–273. doi:10.1159/000343759
De Groot L, Abalovich M, Alexander EK, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012;97(8):2543–2565. doi:10.1210/jc.2011-2803
Crawford NM, Steiner AZ. Thyroid autoimmunity and reproductive function. Semin Reprod Med. 2016;34(6):343–350.
doi:10.1055/s-0036-1593485
Maraka S, Ospina NM, O’Keeffe DT, et al. Subclinical hypothyroidism in pregnancy: a systematic review and meta-analysis. Thyroid. 2016;26(4):580–590. doi:10.1089/thy.2015.0418
Wiles KS, Jarvis S, Nelson-Piercy C. Are we overtreating subclinical hypothyroidism in pregnancy? BMJ. 2015;351:h4726. doi:10.1136/bmj.h4726
Tudela CM, Casey BM, McIntire DD, Cunningham FG. Relationship of subclinical thyroid disease to the incidence of gestational diabetes. Obstet Gynecol. 2012;119(5):983–988.
doi:10.1097/AOG.0b013e318250aeeb
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(2):76–94. doi:10.1159/000362597
Karakosta P, Alegakis D, Georgiou V, et al. Thyroid dysfunction and autoantibodies in early pregnancy are associated with increased risk of gestational diabetes and adverse birth outcomes. J Clin Endocrinol Metab. 2012;97(12):4464–4472. doi:10.1210/jc.2012-2540
Toulis KA, Stagnaro-Green A, Negro R. Maternal subclinical hypothyroidism and gestational diabetes mellitus: a meta-analysis. Endocr Pract. 2014; 20(7):703–714. doi:10.4158/EP13440.RA
van den Boogaard E, Vissenberg R, Land JA, et al. Significance of subclinical thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy: a systematic review. Hum Reprod Update. 2011;17(5):605–619. doi:10.1093/humupd/dmr024
Wilson KL, Casey BM, McIntire DD, Halvorson LM, Cunningham FG. Subclinical thyroid disease and the incidence of hypertension in pregnancy. Obstet Gynecol. 2012;119(2 Pt 1):315–320. doi:10.1097/AOG.0b013e318240de6a
Ashoor G, Maiz N, Rotas M, Jawdat F, Nicolaides KH. Maternal thyroid function at 11 to 13 weeks of gestation and subsequent fetal death. Thyroid. 2010;20(9):989–993. doi:10.1089/thy.2010.0058
Casey BM, Dashe JS, Wells CE, et al. Subclinical hypothyroidism and pregnancy outcomes. Obstet Gynecol. 2005;105(2):239–245. doi:10.1097/01.AOG.0000152345.99421.22
Negro R, Schwartz A, Gismondi R, Tinelli A, Mangieri T, Stagnaro-Green A. Increased pregnancy loss rate in thyroid antibody negative women with TSH levels between 2.5 and 5.0 in the first trimester of pregnancy. J Clin Endocrinol Metab. 2010;95(9):E44–E48. doi:10.1210/jc.2010-0340
Su PY, Huang K, Hao JH, et al. Maternal thyroid function in the first twenty weeks of pregnancy and subsequent fetal and infant development: a prospective population-based cohort study in China. J Clin Endocrinol Metab. 2011;96(10):3234–3241.
doi:10.1210/jc.2011-0274
Allan WC, Haddow JE, Palomaki GE, et al. Maternal thyroid deficiency and pregnancy complications: implications for population screening. J Med Screen. 2000; 7(3):127–130. doi:10.1136/jms.7.3.127
Benhadi N, Wiersinga WM, Reitsma JB, Vrijkotte TG, Bonsel GJ. Higher maternal TSH levels in pregnancy are associated with increased risk for miscarriage, fetal or neonatal death. Eur J Endocrinol. 2009; 160(6):985–991. doi:10.1530/EJE-08-0953
Korevaar TI, Medici M, de Rijke YB, et al. Ethnic differences in maternal thyroid parameters during pregnancy: the generation R study. J Clin Endocrinol Metab. 2013; 98(9):3678–3686. doi:10.1210/jc.2013-2005
Cleary-Goldman J, Malone FD, Lambert-Messerlian G, et al. Maternal thyroid hypofunction and pregnancy outcome. Obstet Gynecol. 2008;112(1):85–92. doi:10.1097/AOG.0b013e3181788dd7
Li Y, Shan Z, Teng W, et al. Abnormalities of maternal thyroid function during pregnancy affect neuropsychological development of their children at 25-30 months. Clin Endocrinol (Oxf). 2010;72(6):825–829. doi:10.1111/j.1365-2265.2009.03743.x
Haddow JE, Palomaki GE, Allan WC, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med. 1999;341(8):549–555. doi:10.1056/NEJM199908193410801
Henrichs J, Bongers-Schokking JJ, Schenk JJ, et al. Maternal thyroid function during early pregnancy and cognitive functioning in early childhood: the generation R study. J Clin Endocrinol Metab. 2010;95(9):4227–4234. doi:10.1210/jc.2010-0415
Behrooz HG, Tohidi M, Mehrabi Y, Behrooz EG, Tehranidoost M, Azizi F. Subclinical hypothyroidism in pregnancy: intellectual development of offspring. Thyroid. 2011;21(10):1143–1147. doi:10.1089/thy.2011.0053
Julvez J, Alvarez-Pedrerol M, Rebagliato M, et al. Thyroxine levels during pregnancy in healthy women and early child neurodevelopment. Epidemiology 2013; 24(1):150–157. doi:10.1097/EDE.0b013e318276ccd3
Casey BM, Thom EA, Peaceman AM, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network. Treatment of subclinical hypothyroidism or hypothyroxinemia in pregnancy. N Engl J Med. 2017;376(9):815–825. doi:10.1056/NEJMoa1606205
Burns RB, Bates CK, Hartzband P, Smetana GW. Should we treat for subclinical hypothyroidism?: Grand rounds discussion from Beth Israel Deaconess Medical Center. Ann Intern Med. 2016; 164(11):764–770. doi:10.7326/M16-0857
Kucukler FK, Akbaba G, Arduc A, Simsek Y, Guler S. Evaluation of the common mistakes made by patients in the use of levothyroxine. Eur J Intern Med. 2014;25(9):e107–e108. doi:10.1016/j.ejim.2014.09.002
Millan M, Rotenberg KS, Vora K, et al. Comorbidities, concomitant medications, and diet as factors affecting levothyroxine therapy: results of the CONTROL surveillance project. Drugs R D. 2016;16(1):53–68. doi:10.1007/s40268-015-0116-6
Pollock MA, Sturrock A, Marshall K, et al. Thyroxine treatment in patients with symptoms of hypothyroidism but thyroid function tests within the reference range: Randomised double blind placebo controlled crossover trial. BMJ. 2001;323(7318):891–895. pmid:11668132
Peeters RP. Subclinical hypothyroidism. N Engl J Med. 2017;376(26):2556–2565. doi:10.1056/NEJMcp1611144