Subclinical hypothyroidism and digit span test performance in children: a systematic review and meta-analysis

  • Nadhea Debrinita Surya School of Medicine and Health Sciences, Atma Jaya Catholic University of Indonesia
  • Nicolas Daniel Widjanarko School of Medicine and Health Sciences, Atma Jaya Catholic University of Indonesia
  • Theressa Kristiayu Permatasari School of Medicine and Health Sciences, Atma Jaya Catholic University of Indonesia
  • Yuliana Yosephine School of Medicine & Health Sciences, Atma Jaya Catholic University of Indonesia
  • Ellen Wijaya, dr. Department of Pediatrics, School of Medicine and Health Sciences, Atma Jaya Catholic University of Indonesia
Keywords: subclinical hypothyroidism; cognitive function; digit span test; children


Background The digit span (DS) test is one of the most commonly used neuropsychological tests to assess certain cognitive domains, i.e., short-term verbal memory, working memory, and attention. Subclinical hypothyroidism (SH) may be associated with a risk of cognitive impairment in children and adolescents.

Objective To evaluate the association between SH and DS test performance in children.

Methods Eligible studies evaluating SH and DS test performance were included in this systematic review and further assessed for risk of bias using the Newcastle Ottawa Scale. We carried out a meta-analysis using the random effects model to determine mean difference with 95% confidence interval (95%CI) for continuous data. This systematic review was conducted according to the Preview Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement.

Results Out of 1,511 participants in the five included studies, 129 had SH and 1,382 were euthyroid.  The quality of all studies were fair to good. Three studies were extracted for meta-analysis, with results showing a trend toward a poorer DS test performance in the SH group compared to controls, although this difference was statistically insignificant (IV -0.57; 95%CI -1.61 to 0.46; P=0.28). There was no significant heterogeneity among the included studies (I2=0%; P=0.69).

Conclusion No significant association was noted between SH and the domains of cognitive function assessed using the DS test. Several intrinsic and extrinsic factors and inability of the DS test to detect subtle impairment may limit its usefulness in children.


1. Woods DL, Kishiyama MM, Yund EW, Herron TJ, Edwards B, Poliva O, et al. Improving digit span assessment of short-term verbal memory. J Clin Exp Neuropsychol. 2011;33:101–11. DOI:
2. de Paula JJ, Malloy-Diniz LF, Romano-Silva MA. Reliability of working memory assessment in neurocognitive disorders: a study of the Digit Span and Corsi Block-Tapping tasks. Rev Bras Psiquiatr Sao Paulo Braz 1999. 2016;38:262–3. DOI:
3. Groth-Marnat G, Baker S. Digit Span as a measure of everyday attention: a study of ecological validity. Percept Mot Skills. 2003;97:1209–18. DOI:
4. Jones G, Macken B. Questioning short-term memory and its measurement: Why digit span measures long-term associative learning. Cognition. 2015 Nov;144:1–13. DOI:
5. Fatourechi V. Subclinical Hypothyroidism: An Update for Primary Care Physicians. Mayo Clin Proc. 2009 ;84:65–71. DOI:
6. Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, et al. Serum TSH, T(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. DOI:
7. Smith JW, Evans AT, Costall B, Smythe JW. Thyroid hormones, brain function and cognition: a brief review. Neurosci Biobehav Rev. 2002;26:45–60. DOI:
8. Salerno M, Capalbo D, Cerbone M, De Luca F. Subclinical hypothyroidism in childhood - current knowledge and open issues. Nat Rev Endocrinol. 2016;12:734–46. DOI:
9. Sangün Ö, Demirci S, Dündar N, Pirgon Ö, Koca T, Do?an M, et al. The effects ofsSix-month L-thyroxine treatment on cognitive functions and event-related brain potentials in children with subclinical hypothyroidism. J Clin Res Pediatr Endocrinol. 2015;7:102–8. DOI:
10. Kudrjavcev T. Neurologic complications of thyroid dysfunction. Adv Neurol. 1978;19:619–36. PMID: 742545.
11. Baldini IM, Vita A, Mauri MC, Amodei V, Carrisi M, Bravin S, et al. Psychopathological and cognitive features in subclinical hypothyroidism. Prog Neuropsychopharmacol Biol Psychiatry. 1997;21:925–35. PMID: 9380789. DOI:
12. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339:b2700. DOI:
13. Ergür AT, Taner Y, Ata E, Melek E, Bakar EE, Sancak T. Neurocognitive functions in children and adolescents with subclinical hypothyroidism. J Clin Res Pediatr Endocrinol. 2012;4:21–4. PMID: 22394701.
14. 9.5.2 Identifying and measuring heterogeneity [Internet]. [cited 2021 Jan 27]. Available from:
15. Atli SK, Dündar NO, Bayazit O, Esin NE, Erdo?an U, Çatli G, et al. Auditory event-related potentials demonstrate early cognitive impairment in children with subclinical hypothyroidism. J Pediatr Endocrinol Metab. 2019;32:689–97. PMID: 31194683. DOI:
16. Capalbo D, Alfano S, Polizzi M, Di Mase R, Improda N, Esposito A, et al. Cognitive function in children with idiopathic subclinical hypothyroidism: effects of 2 years of levothyroxine therapy. J Clin Endocrinol Metab. 2020;105:e774–81. DOI: 10.1210/clinem/dgaa046.
17. Cerbone M, Bravaccio C, Capalbo D, Polizzi M, Wasniewska M, Cioffi D, et al. Linear growth and intellectual outcome in children with long-term idiopathic subclinical hypothyroidism. Eur J Endocrinol. 2011;164:591–7. DOI:
18. Wu T, Flowers JW, Tudiver F, Wilson JL, Punyasavatsut N. Subclinical thyroid disorders and cognitive performance among adolescents in the United States. BMC Pediatr. 2006;6:12. DOI:
19. Learning & Memory [Internet]. [cited 2021 Jan 27]. Available from:
20. Langner R, Eickhoff SB. Sustaining attention to simple tasks: A meta-analytic review of the neural mechanisms of vigilant attention. Psychol Bull. 2013;139:870–900. DOI:
21. Diamond A. Executive Functions. Annu Rev Psychol. 2013;64:135–68. DOI:
22. Davis EE, Landrum J. WISC-R, Wechsler Intelligence Scale for Children—Revised. TPGA J. 1975;4:59–62. DOI:
23. Fink HA, Hemmy LS, MacDonald R, Carlyle MH, Olson CM, Dysken MW, et al. Neuropsychological Test Descriptions [Internet]. Cognitive Outcomes After Cardiovascular Procedures in Older Adults: A Systematic Review [Internet]. Agency for Healthcare Research and Quality (US); 2014 [cited 2021 Jan 27]. Available from: PMID: 25905147.
24. Kirkwood MW, Hargrave DD, Kirk JW. The value of the WISC-IV Digit Span subtest in detecting noncredible performance during pediatric neuropsychological examinations. Arch Clin Neuropsychol Off J Natl Acad Neuropsychol. 2011;26:377–84. DOI:
25. Kumar M, Modi S, Rana P, Kumar P, Kanwar R, Sekhri T, et al. Alteration in intrinsic and extrinsic functional connectivity of resting state networks associated with subclinical hypothyroid. J Neuroendocrinol. 2018. DOI:
26. Bauer M, Silverman DHS, Schlagenhauf F, London ED, Geist CL, van Herle K, et al. Brain glucose metabolism in hypothyroidism: a positron emission tomography study before and after thyroid hormone replacement therapy. J Clin Endocrinol Metab. 2009;94:2922–9. DOI:
27. Zhu DF, Wang ZX, Zhang DR, Pan ZL, He S, Hu XP, et al. fMRI revealed neural substrate for reversible working memory dysfunction in subclinical hypothyroidism. Brain J Neurol. 2006;129(Pt 11):2923–30. DOI:
28. Samuels MH, Schuff KG, Carlson NE, Carello P, Janowsky JS. Health status, mood, and cognition in experimentally induced subclinical hypothyroidism. J Clin Endocrinol Metab. 2007;92:2545–51. DOI:
29. Horn S, Heuer H. Thyroid hormone action during brain development: more questions than answers. Mol Cell Endocrinol. 2010;315:19–26. DOI:
30. Cui Y, Yu J, Zhang B, Guo B, Gao T, Liu H. The relationships between thyroid-stimulating hormone and/or dopamine levels in peripheral blood and IQ in children with different urinary iodine concentrations. Neurosci Lett. 2020 Jun 11;729:134981. DOI:
31. Ma S, Re W, Stein MA, Weiss RE. Thyroid function tests and neurocognitive functioning in children referred for attention deficit/hyperactivity disorder. Psychoneuroendocrinology. 2003;28:304–16. DOI:
32. Baz FE, Hamza RT, El-Din MAS, Hassan MA. Study of thyroid function in children with attention deficit hyperactivity disorder and aggressive behavior. Egypt J Med Hum Genet. 2008;9:93–104.
How to Cite
Surya N, Widjanarko N, Permatasari T, Yosephine Y, Wijaya E. Subclinical hypothyroidism and digit span test performance in children: a systematic review and meta-analysis. PI [Internet]. 31Oct.2022 [cited 30Nov.2022];62(5):324-. Available from:
Pediatric Endocrinology
Received 2021-07-17
Accepted 2022-10-31
Published 2022-10-31