Levothyroxine treatment and pregnancy outcomes in women with subclinical hypothyroidism: a systematic review and meta-analysis

  • Sima Nazarpour
  • Fahimeh Ramezani TehraniEmail author
  • Mina Amiri
  • Razieh Bidhendi Yarandi
  • Fereidoun Azizi



To evaluate the benefits of LT4 treatment on pregnancy outcomes in SCH women.

Study design

PubMed [including Medline], Web of Science, Wiley, Google Scholar, Science direct and Scopus were searched for identifying and retrieving all English articles published up to May 2018 on the effects of levothyroxine treatment on pregnancy outcomes in pregnant women with SCH compared to untreated or healthy controls. In this systematic review and meta-analysis, both fixed and random effect models were applied to estimate the pooled effect size. Heterogeneity and publication bias were evaluated using the I-squared (I2) and Begg’s statistics, respectively. We also explored heterogeneity sources using meta-regression models and sensitivity analysis.


Data of 13 cohort studies and randomized controlled trials with a total of 11,503 participants were analyzed. This meta-analysis showed that pregnant women with SCH treated with levothyroxine had lower chances of pregnancy loss (OR 0.78, 95% CI 0.66–0.94; I2 = 0%) and higher chances for live birth rates (OR 2.72, 95% CI 1.44–5.11; I2 = 25%) than the placebo group. Compared to euthyroid women, SCH patients treated with levothyroxine had higher odds ratio for preterm labor (OR 1.82, 95% CI 1.14–2.91; I2 = 0%).


Results of this study showed that the effects of treatment with levothyroxine in SCH pregnant women are not the same for all pregnancy outcomes. Levothyroxine treatment in these patients can reduce pregnancy loss. Considering the limited number of studies available, further studies are warranted to document more precise data on other consequences.


Subclinical hypothyroidism Pregnancy Outcome Treatment 



The authors wish to acknowledge Ms. Niloofar Shiva for critical editing of English grammar and syntax of the manuscript.

Author contributions

SN was involved in study design, search in databases, studies selection, data analysis, manuscript drafting, and submitting manuscript. FRT was involved in study design, data analysis, manuscript drafting and critical discussions. MA contributed in data analysis, and critical discussion, execution and manuscript drafting. RBY contributed in statistical analysis, interpreting data and manuscript drafting. FA was involved in data analysis, manuscript drafting, revising and critical discussion.


This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This systematic review and meta-analysis study was approved by the ethics committee of the Research Institute of Endocrine Sciences (RIES) (approval no.: IR.SBMU.ENDOCRINE.REC.1397.126).

Supplementary material

404_2019_5245_MOESM1_ESM.docx (174 kb)
Supplementary material 1 (DOCX 173 kb)


  1. 1.
    Maraka S, Ospina NM, O’Keeffe DT, Espinosa De Ycaza AE, Gionfriddo MR, Erwin PJ, Coddington CC 3rd, Stan MN, Murad MH, Montori VM (2016) Subclinical hypothyroidism in pregnancy: a systematic review and meta-analysis. Thyroid 26(4):580–590CrossRefGoogle Scholar
  2. 2.
    Al Shanqeeti SA, Alkhudairy YN, Alabdulwahed AA, Ahmed AE, Al-Adham MS, Mahmood NM (2018) Prevalence of subclinical hypothyroidism in pregnancy in Saudi Arabia. Saudi Med J 39(3):254–260CrossRefGoogle Scholar
  3. 3.
    Garmendia Madariaga A, Santos Palacios S, Guillen-Grima F, Galofre JC (2014) The incidence and prevalence of thyroid dysfunction in Europe: a meta-analysis. J Clin Endocrinol Metab 99(3):923–931CrossRefGoogle Scholar
  4. 4.
    Chen LM, Du WJ, Dai J, Zhang Q, Si GX, Yang H, Ye EL, Chen QS, Yu LC, Zhang C, Lu XM (2014) Effects of subclinical hypothyroidism on maternal and perinatal outcomes during pregnancy: a single-center cohort study of a Chinese population. PLoS One 9(10):e109364CrossRefGoogle Scholar
  5. 5.
    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):3234–3241CrossRefGoogle Scholar
  6. 6.
    Tudela CM, Casey BM, McIntire DD, Cunningham FG (2012) Relationship of subclinical thyroid disease to the incidence of gestational diabetes. Obstet Gynecol 119(5):983–988CrossRefGoogle Scholar
  7. 7.
    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):322–325Google Scholar
  8. 8.
    Negro R, Schwartz A, Gismondi R, Tinelli A, Mangieri T, Stagnaro-Green A (2010) 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 95 (9):E44–E48.
  9. 9.
    Negro R, Schwartz A, Gismondi R, Tinelli A, Mangieri T, Stagnaro-Green A (2010) Universal screening versus case finding for detection and treatment of thyroid hormonal dysfunction during pregnancy. J Clin Endocrinol Metab 95(4):1699–1707CrossRefGoogle Scholar
  10. 10.
    Maraka S, Singh Ospina NM, O’Keeffe DT, Rodriguez-Gutierrez R, Espinosa De Ycaza AE, Wi CI, Juhn YJ, Coddington CC 3rd, Montori VM, Stan MN (2016) Effects of levothyroxine therapy on pregnancy outcomes in women with subclinical hypothyroidism. Thyroid 26(7):980–986CrossRefGoogle Scholar
  11. 11.
    Nazarpour S, Ramezani Tehrani F, Simbar M, Tohidi M, Minooee S, Rahmati M, Azizi F (2018) Effects of levothyroxine on pregnant women with subclinical hypothyroidism, negative for thyroid peroxidase antibodies. J Clin Endocrinol Metab 103(3):926–935CrossRefGoogle Scholar
  12. 12.
    Nazarpour S, Ramezani Tehrani F, Simbar M, Tohidi M, Alavi Majd H, Azizi F (2017) Effects of levothyroxine treatment on pregnancy outcomes in pregnant women with autoimmune thyroid disease. Eur J Endocrinol 176(2):253–265CrossRefGoogle Scholar
  13. 13.
    Casey BM, Thom EA, Peaceman AM, Varner MW, Sorokin Y, Hirtz DG, Reddy UM, Wapner RJ, Thorp JM Jr., Saade G, Tita AT, Rouse DJ, Sibai B, Iams JD, Mercer BM, Tolosa J, Caritis SN, VanDorsten JP, Eunice Kennedy Shriver National Institute of Child H, Human Development Maternal-Fetal Medicine Units N (2017) Treatment of subclinical hypothyroidism or hypothyroxinemia in pregnancy. N Engl J Med 376(9):815–825CrossRefGoogle Scholar
  14. 14.
    Ma L, Qi H, Chai X, Jiang F, Mao S, Liu J, Zhang S, Lian X, Sun X, Wang D, Ren J, Yan Q (2016) The effects of screening and intervention of subclinical hypothyroidism on pregnancy outcomes: a prospective multicenter single-blind, randomized, controlled study of thyroid function screening test during pregnancy. J Matern Fetal Neonatal Med 29(9):1391–1394Google Scholar
  15. 15.
    Nasirkandy MP, Badfar G, Shohani M, Rahmati S, YektaKooshali MH, Abbasalizadeh S, Soleymani A, Azami M (2017) The relation of maternal hypothyroidism and hypothyroxinemia during pregnancy on preterm birth: an updated systematic review and meta-analysis. Int J Reprod Biomed 15(9):543–552CrossRefGoogle Scholar
  16. 16.
    Toulis KA, Goulis DG, Venetis CA, Kolibianakis EM, Negro R, Tarlatzis BC, Papadimas I (2010) Risk of spontaneous miscarriage in euthyroid women with thyroid autoimmunity undergoing IVF: a meta-analysis. Eur J Endocrinol 162(4):643–652CrossRefGoogle Scholar
  17. 17.
    Zhang Y, Wang H, Pan X, Teng W, Shan Z (2017) Patients with subclinical hypothyroidism before 20 weeks of pregnancy have a higher risk of miscarriage: a systematic review and meta-analysis. PLoS One 12(4):e0175708CrossRefGoogle Scholar
  18. 18.
    Velkeniers B, Van Meerhaeghe A, Poppe K, Unuane D, Tournaye H, Haentjens P (2013) Levothyroxine treatment and pregnancy outcome in women with subclinical hypothyroidism undergoing assisted reproduction technologies: systematic review and meta-analysis of RCTs. Hum Reprod Update 19(3):251–258CrossRefGoogle Scholar
  19. 19.
    Alexander EK, Pearce EN, Brent GA, Brown RS, Chen H, Dosiou C, Grobman WA, Laurberg P, Lazarus JH, Mandel SJ, Peeters RP, Sullivan S (2017) 2017 guidelines of the american thyroid association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid 27(3):315–389CrossRefGoogle Scholar
  20. 20.
    Lazarus J, Brown RS, Daumerie C, Hubalewska-Dydejczyk A, Negro R, Vaidya B (2014) 2014 European thyroid association guidelines for the management of subclinical hypothyroidism in pregnancy and in children. Eur Thyroid J 3(2):76–94CrossRefGoogle Scholar
  21. 21.
    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):2543–2565CrossRefGoogle Scholar
  22. 22.
    Stang A (2010) Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 25(9):603–605CrossRefGoogle Scholar
  23. 23.
    Schulz KF, Altman DG, Moher D (2010) CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMC Med 8(1):18CrossRefGoogle Scholar
  24. 24.
    Abdel Rahman AH, Aly Abbassy H, Abbassy AA (2010) Improved in vitro fertilization outcomes after treatment of subclinical hypothyroidism in infertile women. Endocr Pract 16(5):792–797CrossRefGoogle Scholar
  25. 25.
    Cai Y, Zhong L, Guan J, Guo R, Niu B, Ma Y, Su H (2017) Outcome of in vitro fertilization in women with subclinical hypothyroidism. Reprod Biol Endocrinol 15(1):39CrossRefGoogle Scholar
  26. 26.
    Kim CH, Ahn JW, Kang SP, Kim SH, Chae HD, Kang BM (2011) Effect of levothyroxine treatment on in vitro fertilization and pregnancy outcome in infertile women with subclinical hypothyroidism undergoing in vitro fertilization/intracytoplasmic sperm injection. Fertil Steril 95(5):1650–1654CrossRefGoogle Scholar
  27. 27.
    Al-Anbari L A (2017) Thyroxine Supplementation Improve Intrauterine Insemination Outcome in patients with subclinical Hypothyroidism. J Pharm Sci Res 9(10):1768–1772.
  28. 28.
    Bernardi LA, Cohen RN, Stephenson MD (2013) Impact of subclinical hypothyroidism in women with recurrent early pregnancy loss. Fertil Steril 100(5):1326–1331CrossRefGoogle Scholar
  29. 29.
    Pearce E, Oken E, Gillman M, Lee S, Magnani B, Platek D, Braverman L (2008) Association of first-trimester thyroid function test values with thyroperoxidase antibody status, smoking, and multivitamin use. Endocrine Pract 14(1):33–39CrossRefGoogle Scholar
  30. 30.
    Banerjee S (2011) Thyroid disorders in pregnancy. J Assoc Physicians India 59(Suppl):32–34Google Scholar
  31. 31.
    Weetman AP (2010) Immunity, thyroid function and pregnancy: molecular mechanisms. Nat Rev Endocrinol 6(6):311–318CrossRefGoogle Scholar
  32. 32.
    Sailakshmi M, Rekha B, Akash SS (2014) Autoimmune thyroid disease in pregnancy. Int J Reprod Contracept Obstetr Gynecol 3(2):321–324CrossRefGoogle Scholar
  33. 33.
    Sheehan PM, Nankervis A, Araujo Junior E, Da Silva Costa F (2015) Maternal thyroid disease and preterm birth: systematic review and meta-analysis. J Clin Endocrinol Metab 100(11):4325–4331CrossRefGoogle Scholar
  34. 34.
    Wang H, Gao H, Chi H, Zeng L, Xiao W, Wang Y, Li R, Liu P, Wang C, Tian Q, Zhou Z, Yang J, Liu Y, Wei R, Mol BWJ, Hong T, Qiao J (2017) Effect of levothyroxine on miscarriage among women with normal thyroid function and thyroid autoimmunity undergoing in vitro fertilization and embryo transfer: a randomized clinical trial. JAMA 318(22):2190–2198CrossRefGoogle Scholar
  35. 35.
    Khatiwada S, Sah SK, Kc R, Baral N, Lamsal M (2016) Thyroid dysfunction in metabolic syndrome patients and its relationship with components of metabolic syndrome. Clin Diabetes Endocrinol 2(1):3CrossRefGoogle Scholar
  36. 36.
    Rao M, Zeng Z, Zhou F, Wang H, Liu J, Wang R, Wen Y, Yang Z, Su C, Su Z, Zhao S, Tang L (2019) Effect of levothyroxine supplementation on pregnancy loss and preterm birth in women with subclinical hypothyroidism and thyroid autoimmunity: a systematic review and meta-analysis. Hum Reprod Update 25(3):344–361CrossRefGoogle Scholar
  37. 37.
    Duan Y, Peng W, Wang X, Tang W, Liu X, Xu S, Mao X, Feng S, Feng Y, Qin Y, Xu K, Liu C, Liu C (2009) Community-based study of the association of subclinical thyroid dysfunction with blood pressure. Endocrine 35(2):136–142CrossRefGoogle Scholar
  38. 38.
    Breathnach FM, Donnelly J, Cooley SM, Geary M, Malone FD (2013) Subclinical hypothyroidism as a risk factor for placental abruption: evidence from a low-risk primigravid population. Aust N Z J Obstet Gynaecol 53(6):553–560CrossRefGoogle Scholar
  39. 39.
    Debieve F, Duliere S, Bernard P, Hubinont C, De Nayer P, Daumerie C (2009) To treat or not to treat euthyroid autoimmune disorder during pregnancy? Gynecol Obstet Invest 67(3):178–182CrossRefGoogle Scholar
  40. 40.
    He X, Wang P, Wang Z, He X, Xu D, Wang B (2012) Thyroid antibodies and risk of preterm delivery: a meta-analysis of prospective cohort studies. Eur J Endocrinol 167(4):455–464CrossRefGoogle Scholar
  41. 41.
    Triggianese P, Perricone C, Conigliaro P, Chimenti MS, Perricone R, De Carolis C (2016) Peripheral blood natural killer cells and mild thyroid abnormalities in women with reproductive failure. Int J Immunopathol Pharmacol 29(1):65–75CrossRefGoogle Scholar
  42. 42.
    Zhao L, Jiang G, Tian X, Zhang X, Zhu T, Chen B, Wang Y, Ma Q (2018) Initiation timing effect of levothyroxine treatment on subclinical hypothyroidism in pregnancy. Gynecol Endocrinol 34(10):845–848CrossRefGoogle Scholar
  43. 43.
    Stagnaro-Green A, Abalovich M, Alexander E, Azizi F, Mestman J, Negro R, Nixon A, Pearce EN, Soldin OP, Sullivan S, Wiersinga W, American Thyroid Association Taskforce on Thyroid Disease During P, Postpartum (2011) Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 21(10):1081–1125CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of MidwiferyIslamic Azad University, Varamin-Pishva BranchTehranIran
  2. 2.Reproductive Endocrinology Research Center, Research Institute for Endocrine SciencesShahid Beheshti University of Medical SciencesTehranIran
  3. 3.Department of Epidemiology and Biostatistics, School of Public HealthTehran University of Medical SciencesTehranIran
  4. 4.Endocrine Research Center, Research Institute for Endocrine SciencesShahid Beheshti University of Medical SciencesTehranIran

Personalised recommendations