Skip to main content
Log in

Update on a new controversy in endocrinology: isolated maternal hypothyroxinemia

  • Review
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Isolated hypothyroxinemia (IH) is defined as a thyroxine level in the lower 5th (severe IH) or 10th percentile (mild IH) of the pregnancy-related reference range and a normal TSH. The etiology of IH remains unknown. This review aims to evaluate the biochemical criteria used to define IH in different published studies and to discuss potential maternal as well as fetal outcomes and whether treatment during early pregnancy can prevent the eventual adverse effects. For the current literature a better standardization of free thyroxine assays is needed, as well as the use of appropriated trimester-specific reference intervals for thyroid function tests. Today no study demonstrates a benefit from treating early pregnant IH women on perinatal and fetal outcomes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Stagnaro-Green A, Abalovich M, Alexander E, Azizi F, Mestman J, Negro R, Nixon A, Pearce EN, Soldin OP, Sullivan S, Wiersinga W (2011) American Thyroid Association Taskforce on Thyroid Disease During P, Postpartum Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid: Off J Am Thyroid Assoc 21(10):1081–1125. doi:10.1089/thy.2011.0087

    Article  Google Scholar 

  2. Man EB (1972) Thyroid function in pregnancy and infancy. Maternal hypothyroxinemia and retardation of progeny. CRC Crit Rev Clin Lab Sci 3(2):203–225

    Article  CAS  PubMed  Google Scholar 

  3. Glinoer D (1997) The regulation of thyroid function in pregnancy: pathways of endocrine adaptation from physiology to pathology. Endocr Rev 18(3):404–433. doi:10.1210/edrv.18.3.0300

    Article  CAS  PubMed  Google Scholar 

  4. Stricker R, Echenard M, Eberhart R, Chevailler MC, Perez V, Quinn FA, Stricker R (2007) Evaluation of maternal thyroid function during pregnancy: the importance of using gestational age-specific reference intervals. Eur J Endocrinol/Eur Fed Endocrine Soc 157(4):509–514. doi:10.1530/EJE-07-0249

    Article  CAS  Google Scholar 

  5. Ekinci EI, Lu ZX, Sikaris K, Bittar I, Cheong KY, Lam Q, Crinis N, Houlihan CA (2013) Longitudinal assessment of thyroid function in pregnancy. Ann Clin Biochem 50(Pt 6):595–602. doi:10.1177/0004563213486450

    Article  PubMed  Google Scholar 

  6. Li Y, Shan Z, Teng W, Yu X, Li Y, Fan C, Teng X, Guo R, Wang H, Li J, Chen Y, Wang W, Chawinga M, Zhang L, Yang L, Zhao Y, Hua T (2010) Abnormalities of maternal thyroid function during pregnancy affect neuropsychological development of their children at 25–30 months. Clin Endocrinol 72(6):825–829. doi:10.1111/j.1365-2265.2009.03743.x

    Article  CAS  Google Scholar 

  7. Roti E, Gardini E, Minelli R, Bianconi L, Flisi M (1991) Thyroid function evaluation by different commercially available free thyroid hormone measurement kits in term pregnant women and their newborns. J Endocrinol Invest 14(1):1–9

    Article  CAS  PubMed  Google Scholar 

  8. Kahric-Janicic N, Soldin SJ, Soldin OP, West T, Gu J, Jonklaas J (2007) Tandem mass spectrometry improves the accuracy of free thyroxine measurements during pregnancy. Thyroid: Off J Am Thyroid Assoc 17(4):303–311. doi:10.1089/thy.2006.0303

    Article  CAS  Google Scholar 

  9. Lee RH, Spencer CA, Mestman JH, Miller EA, Petrovic I, Braverman LE, Goodwin TM (2009) Free T4 immunoassays are flawed during pregnancy. Am J Obstet Gynecol 200(3):260 e261–266. doi:10.1016/j.ajog.2008.10.042

  10. Bliddal S, Feldt-Rasmussen U, Boas M, Faber J, Juul A, Larsen T, Precht DH (2014) Gestational age-specific reference ranges from different laboratories misclassify pregnant women’s thyroid status: comparison of two longitudinal prospective cohort studies. Eur J Endocrinol/Eur Fed Endocr Soc 170(2):329–339. doi:10.1530/EJE-13-0672

    Article  CAS  Google Scholar 

  11. Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I, Mechanick JI, Pessah-Pollack R, Singer PA, Woeber KA (2012) 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 18(6):988–1028

    Article  PubMed  Google Scholar 

  12. Midgley JE, Hoermann R (2013) Measurement of total rather than free thyroxine in pregnancy: the diagnostic implications. Thyroid: Off J Am Thyroid Assoc 23(3):259–261. doi:10.1089/thy.2012.0469

    Article  CAS  Google Scholar 

  13. Soldin OP (2012) When thyroidologists agree to disagree: comments on the 2012 Endocrine Society pregnancy and thyroid disease clinical practice guideline. J Clin Endocrinol Metab 97(8):2632–2635. doi:10.1210/jc.2012-2529

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Soldin OP, Tractenberg RE, Hollowell JG, Jonklaas J, Janicic N, Soldin SJ (2004) Trimester-specific changes in maternal thyroid hormone, thyrotropin, and thyroglobulin concentrations during gestation: trends and associations across trimesters in iodine sufficiency. Thyroid: Off J Am Thyroid Assoc 14(12):1084–1090. doi:10.1089/thy.2004.14.1084

    Article  CAS  Google Scholar 

  15. Petrović Ivana M, Savin S, Spasić S, Cvejić Dubravka S, Paunković N, Paunković J (2005) The T4/TBG ratio in healthy subjects and in patients with disorders of thyroid function: correlation with FT4 concentrations Jugoslovenska Medicinska Biohemija 24(4):241–246 doi:10.2298/JMH0504241P

  16. Moleti M, Trimarchi F, Vermiglio F (2011) Doubts and concerns about isolated maternal hypothyroxinemia. J Thyroid Res 2011:463029. doi:10.4061/2011/463029

    Article  PubMed Central  PubMed  Google Scholar 

  17. Brucker-Davis F, Panaia-Ferrari P, Gal J, Fenichel P, Hieronimus S (2013) Iodine supplementation throughout pregnancy does not prevent the drop in FT4 in the second and third trimesters in women with normal initial thyroid function. Eur Thyroid J 2(3):187–194. doi:10.1159/000350882

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Zimmermann MB (2012) The effects of iodine deficiency in pregnancy and infancy. Paediatr Perinat Epidemiol 26(Suppl 1):108–117. doi:10.1111/j.1365-3016.2012.01275.x

    Article  PubMed  Google Scholar 

  19. Pop VJ, Brouwers EP, Vader HL, Vulsma T, van Baar AL, de Vijlder JJ (2003) Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study. Clin Endocrinol 59(3):282–288

    Article  Google Scholar 

  20. Pop VJ, de Vries E, van Baar AL, Waelkens JJ, de Rooy HA, Horsten M, Donkers MM, Komproe IH, van Son MM, Vader HL (1995) Maternal thyroid peroxidase antibodies during pregnancy: a marker of impaired child development? J Clin Endocrinol Metab 80(12):3561–3566. doi:10.1210/jcem.80.12.8530599

    Article  CAS  PubMed  Google Scholar 

  21. Utiger RD (1999) Maternal hypothyroidism and fetal development. New England J Med 341(8):601–602. doi:10.1056/NEJM199908193410809

    Article  CAS  Google Scholar 

  22. Shan ZY, Chen YY, Teng WP, Yu XH, Li CY, Zhou WW, Gao B, Zhou JR, Ding B, Ma Y, Wu Y, Liu Q, Xu H, Liu W, Li J, Wang WW, Li YB, Fan CL, Wang H, Guo R, Zhang HM (2009) A study for maternal thyroid hormone deficiency during the first half of pregnancy in China. Eur J Clin Invest 39(1):37–42. doi:10.1111/j.1365-2362.2008.02055.x

    Article  CAS  PubMed  Google Scholar 

  23. Henrichs J, Ghassabian A, Peeters RP, Tiemeier H (2013) Maternal hypothyroxinemia and effects on cognitive functioning in childhood: how and why? Clin Endocrinol 79(2):152–162. doi:10.1111/cen.12227

    Article  Google Scholar 

  24. Lazarus JH, Brown RS, Daumerie C, Hubelewska-Dydejczyk A, Negro R, Vaidya B (2014) European Thyroid Association Guidelines for the Managemenet of Subclinical Hypothyroidism in Pregancy and in Children. Eur Thyroid J 3:76–94

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Wang S, Teng WP, Li JX, Wang WW, Shan ZY (2012) Effects of maternal subclinical hypothyroidism on obstetrical outcomes during early pregnancy. J Endocrinol Invest 35(3):322–325. doi:10.3275/7772

    CAS  PubMed  Google Scholar 

  26. Casey BM, Dashe JS, Spong CY, McIntire DD, Leveno KJ, Cunningham GF (2007) Perinatal significance of isolated maternal hypothyroxinemia identified in the first half of pregnancy. Obstet Gynecol 109(5):1129–1135. doi:10.1097/01.AOG.0000262054.03531.24

    Article  PubMed  Google Scholar 

  27. Hamm MP, Cherry NM, Martin JW, Bamforth F, Burstyn I (2009) The impact of isolated maternal hypothyroxinemia on perinatal morbidity. J Obstet Gynaecol Can 31(11):1015–1021

    PubMed  Google Scholar 

  28. Cleary-Goldman J, Malone FD, Lambert-Messerlian G, Sullivan L, Canick J, Porter TF, Luthy D, Gross S, Bianchi DW, D’Alton ME (2008) Maternal thyroid hypofunction and pregnancy outcome. Obstet Gynecol 112(1):85–92. doi:10.1097/AOG.0b013e3181788dd7

    Article  PubMed  Google Scholar 

  29. Pop VJ, Brouwers EP, Wijnen H, Oei G, Essed GG, Vader HL (2004) Low concentrations of maternal thyroxin during early gestation: a risk factor of breech presentation? BJOG: Int J Obstet Gynaecol 111(9):925–930. doi:10.1111/j.1471-0528.2004.00213.x

    Article  CAS  Google Scholar 

  30. van Mil NH, Steegers-Theunissen RP, Bongers-Schokking JJ, El Marroun H, Ghassabian A, Hofman A, Jaddoe VW, Visser TJ, Verhulst FC, de Rijke YB, Steegers EA, Tiemeier H (2012) Maternal hypothyroxinemia during pregnancy and growth of the fetal and infant head. Reprod Sci 19(12):1315–1322. doi:10.1177/193371911245033

    Article  PubMed  Google Scholar 

  31. Korevaar TI, Schalekamp-Timmermans S, de Rijke YB, Visser WE, Visser W, de Muinck Keizer-Schrama SM, Hofman A, Ross HA, Hooijkaas H, Tiemeier H, Bongers-Schokking JJ, Jaddoe VW, Visser TJ, Steegers EA, Medici M, Peeters RP (2013) Hypothyroxinemia and TPO-antibody positivity are risk factors for premature delivery: the generation R study. J Clin Endocrinol Metab 98(11):4382–4390. doi:10.1210/jc.2013-2855

    Article  CAS  PubMed  Google Scholar 

  32. Su PY, Huang K, Hao JH, Xu YQ, Yan SQ, Li T, Xu YH, Tao FB (2011) 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 96(10):3234–3241. doi:10.1210/jc.2011-0274

    Article  CAS  PubMed  Google Scholar 

  33. Girling JC (1996) Thyroid disease and pregnancy. Br J Hosp Med 56(7):316–320

    CAS  PubMed  Google Scholar 

  34. Lavado-Autric R, Auso E, Garcia-Velasco JV, Arufe Mdel C, Escobar del Rey F, Berbel P, Morreale de Escobar G (2003) Early maternal hypothyroxinemia alters histogenesis and cerebral cortex cytoarchitecture of the progeny. J Clin Invest 111(7):1073–1082. doi:10.1172/JCI16262

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Kooistra L, Crawford S, van Baar AL, Brouwers EP, Pop VJ (2006) Neonatal effects of maternal hypothyroxinemia during early pregnancy. Pediatrics 117(1):161–167. doi:10.1542/peds.2005-0227

    Article  PubMed  Google Scholar 

  36. Henrichs J, Bongers-Schokking JJ, Schenk JJ, Ghassabian A, Schmidt HG, Visser TJ, Hooijkaas H, de Muinck Keizer-Schrama SM, Hofman A, Jaddoe VV, Visser W, Steegers EA, Verhulst FC, de Rijke YB, Tiemeier H (2010) Maternal thyroid function during early pregnancy and cognitive functioning in early childhood: the generation R study. J Clin Endocrinol Metab 95(9):4227–4234. doi:10.1210/jc.2010-0415

    Article  CAS  PubMed  Google Scholar 

  37. Ghassabian A, El Marroun H, Peeters RP, Jaddoe VW, Hofman A, Verhulst FC, Tiemeier H, White T (2014) Downstream effects of maternal hypothyroxinemia in early pregnancy: nonverbal IQ and brain morphology in school-age children. J Clin Endocrinol Metab 99(7):2383–2390. doi:10.1210/jc.2013-4281

    Article  CAS  PubMed  Google Scholar 

  38. Craig WY, Allan WC, Kloza EM, Pulkkinen AJ, Waisbren S, Spratt DI, Palomaki GE, Neveux LM, Haddow JE (2012) Mid-gestational maternal free thyroxine concentration and offspring neurocognitive development at age two years. J Clin Endocrinol Metab 97(1):E22–E28. doi:10.1210/jc.2011-1772

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Vermiglio F, Lo Presti VP, Moleti M, Sidoti M, Tortorella G, Scaffidi G, Castagna MG, Mattina F, Violi MA, Crisa A, Artemisia A, Trimarchi F (2004) Attention deficit and hyperactivity disorders in the offspring of mothers exposed to mild-moderate iodine deficiency: a possible novel iodine deficiency disorder in developed countries. J Clin Endocrinol Metab 89(12):6054–6060. doi:10.1210/jc.2004-0571

    Article  CAS  PubMed  Google Scholar 

  40. Roman GC, Ghassabian A, Bongers-Schokking JJ, Jaddoe VW, Hofman A, de Rijke YB, Verhulst FC, Tiemeier H (2013) Association of gestational maternal hypothyroxinemia and increased autism risk. Ann Neurol 74(5):733–742. doi:10.1002/ana.23976

    Article  CAS  PubMed  Google Scholar 

  41. Hoshiko S, Grether JK, Windham GC, Smith D, Fessel K (2011) Are thyroid hormone concentrations at birth associated with subsequent autism diagnosis? Autism Res: Off J Int Soc Autism Res 4(6):456–463. doi:10.1002/aur.219

    Article  Google Scholar 

  42. Lazarus JH, Bestwick JP, Channon S, Paradice R, Maina A, Rees R, Chiusano E, John R, Guaraldo V, George LM, Perona M, Dall’Amico D, Parkes AB, Joomun M, Wald NJ (2012) Antenatal thyroid screening and childhood cognitive function. New England J Med 366(6):493–501. doi:10.1056/NEJMoa1106104

    Article  CAS  Google Scholar 

  43. Brent GA (2012) Diagnosing thyroid dysfunction in pregnant women: is case finding enough? J Clin Endocrinol Metab 92(1):39–41

    Article  Google Scholar 

  44. De Groot L, Abalovich M, Alexander EK, Amino N, Barbour L, Cobin RH, Eastman CJ, Lazarus JH, Luton D, Mandel SJ, Mestman J, Rovet J, Sullivan S (2012) Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 97(8):2543–2565. doi:10.1210/jc.2011-2803

    Article  PubMed  Google Scholar 

  45. Stagnaro-Green A (2014) Subclinical hypothyroidism and pregancy: the intersection of science, the Art of Medicine and Public Health Policy. Eur Thyroid J 3:73–75

    Article  PubMed Central  PubMed  Google Scholar 

  46. Pop VJ, Kuijpens JL, van Baar AL, Verkerk G, van Son MM, de Vijlder JJ, Vulsma T, Wiersinga WM, Drexhage HA, Vader HL (1999) Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clin Endocrinol 50(2):149–155

    Article  CAS  Google Scholar 

  47. Vaidya B, Anthony S, Bilous M, Shields B, Drury J, Hutchison S, Bilous R (2007) Detection of thyroid dysfunction in early pregnancy: universal screening or targeted high-risk case finding? J Clin Endocrinol Metab 92(1):203–207. doi:10.1210/jc.2006-1748

    Article  CAS  PubMed  Google Scholar 

  48. Moleti M, Lo Presti VP, Mattina F, Mancuso A, De Vivo A, Giorgianni G, Di Bella B, Trimarchi F, Vermiglio F (2009) Gestational thyroid function abnormalities in conditions of mild iodine deficiency: early screening versus continuous monitoring of maternal thyroid status. Eur J Endocrinol/Eur Federat Endocr Soc 160(4):611–617. doi:10.1530/EJE-08-0709

    Article  CAS  Google Scholar 

  49. Berbel P, Mestre JL, Santamaria A, Palazon I, Franco A, Graells M, Gonzalez-Torga A, de Escobar GM (2009) Delayed neurobehavioral development in children born to pregnant women with mild hypothyroxinemia during the first month of gestation: the importance of early iodine supplementation. Thyroid 19(5):511–519. doi:10.1089/thy.2008.0341

    Article  CAS  PubMed  Google Scholar 

  50. Krassas GE, Poppe K, Glinoer D (2010) Thyroid function and human reproductive health. Endocr Rev 31(5):702–755. doi:10.1210/er.2009-0041

    Article  CAS  PubMed  Google Scholar 

  51. Oken E, Braverman LE, Platek D, Mitchell ML, Lee SL, Pearce EN (2009) Neonatal thyroxine, maternal thyroid function, and child cognition. J Clin Endocrinol Metab 94(2):497–503. doi:10.1210/jc.2008-0936

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Chevrier J, Harley KG, Kogut K, Holland N, Johnson C, Eskenazi B (2011) Maternal thyroid function during the second half of pregnancy and child neurodevelopment at 6, 12, 24, and 60 months of age. J Thyroid Res 2011:426427. doi:10.4061/2011/426427

    Article  PubMed Central  PubMed  Google Scholar 

  53. Julvez J, Alvarez-Pedrerol M, Rebagliato M, Murcia M, Forns J, Garcia-Esteban R, Lertxundi N, Espada M, Tardon A, Riano Galan I, Sunyer J (2013) Thyroxine levels during pregnancy in healthy women and early child neurodevelopment. Epidemiology 24(1):150–157. doi:10.1097/EDE.0b013e318276ccd3

    Article  PubMed  Google Scholar 

Download references

Conflict of interest

Authors declare no conflicts of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to C. Daumerie.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Furnica, R.M., Lazarus, J.H., Gruson, D. et al. Update on a new controversy in endocrinology: isolated maternal hypothyroxinemia. J Endocrinol Invest 38, 117–123 (2015). https://doi.org/10.1007/s40618-014-0203-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40618-014-0203-5

Keywords

Navigation