The Relationship of Maternal Subclinical Hypothyroidism during Pregnancy and Preterm Birth: A Systematic Review and Meta-Analysis of Cohort Studies

Document Type : Review Article


1 M.Sc. in Nursing, Faculty of Nursing and Midwifery, Ahvaz Jundishapour University of Medical Science, Ahvaz, Iran.

2 Assistant Professor, Department of Cardiology, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran.

3 Assistant Professor, Department of Internal Medicine, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran.

4 BC of Radiology, Student Research Committee, Faculty of Nursing, Midwifery and Paramedicine of East Gilan, Gilan University of Medical Sciences, Rasht, Iran.

5 Medical Student, Student Research Committee, Ilam University of Medical Sciences, Ilam, Iran


Introduction: The relationship between maternal subclinical hypothyroidism during pregnancy and preterm birth is still not clear and the results of previous studies have been inconsistently reported. This study was performed with aim to assess the relationship between mother's subclinical hypothyroidism during pregnancy and preterm.
Methods: This study was conducted based on preferred reporting items for systematic reviews and meta-analyses (PRISMA) checklist. Review and searching of the literatures were done by two researchers independently in databases such as Scopus, PubMed, ScienceDirect, Embase, Springer, Web of Science, CINAHL, Wiley Online Library, Cochrane Library, EBSCO and Google scholar till June 2017 with standard English MeSH keywords including Thyroid Disease, Hypothyroidism, Subclinical Hypothyroidism, Preterm Delivery, Preterm Labor, Preterm Birth, Premature Delivery, Premature Labor and Premature Birth. Random-effects size based on Cochrane test and I2 were used to pool relative risk (RR) and estimate 95% Confidence Interval (CI). Data were analyzed by Comprehensive Meta-Analysis software ver. 2 software.
Results: Seventeen studies with 3,580 experimental and 64,885 control sample size were included. The RR of preterm birth for pregnant women with subclinical hypothyroidism compared with health group was 1.36 (95% CI: 1.09-1.68, P=0.005) and was statistically significant. RR for this relationship in Asian studies was estimated 1.60 (95% CI: 1.12-2.29, P=0.009) and was statistically significant, but this significant relationship was not found in American (P=0.576) and European (P=0.072) studies.
Conclusion: The incidence of preterm birth for pregnant women with subclinical hypothyroidism was higher compared to euthyroid pregnant women and this relationship was significant. Therefore, physicians should consider the management of these patients in terms of adverse pregnancy outcomes such as preterm birth.


  1. Seyedoshohadaie F, Nouroozi S, Shahgheibi S, Mohammadbeigi R, Sufizadeh N, Rezaei M. Evaluation of prevalence of Thyroid Peroxidase Antibody and therapeutic effect of levothyroxine on pregnancy outcome in positive antibody pregnant women. Iran J Obstet Gynecol Infertil 2014; 17(110):1-7. (Persian).
  2. Mullur R, Liu YY, Brent GA. Thyroid hormone regulation of metabolism. Physiol Rev 2014; 94(2):355–82.
  3. Glinoer D. The regulation of thyroid function in pregnancy: pathways of endocrine adaptation from physiology to pathology. Endocr Rev 1997; 18(3):404–33.
  4. Karakosta P, Alegakis D, Georgiou V, Roumeliotaki T, Fthenou E, Vassilaki M, 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):4464–72.
  5. Skjoldebrand L, Brundin J, Carlstrom A, Pettersson T. Thyroid associated components in serum during normal pregnancy. Acta Endocrinol (Copenh) 1982; 100(4):504–11.
  6. Cignini P, Cafa EV, Giorlandino C, Capriglione S, Spata A, Dugo N. Thyroid physiology and common diseases in pregnancy: review of literature. J Prenat Med 2012; 6(4):64-71.
  7. 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.
  8. Negro R, Mestman JH. Thyroid disease in pregnancy. Best Pract Res Clin Endocrinol Metab 2011; 25(6):927-43.
  9. Allan WC, Haddow JE, Palomaki GE, Williams JR, Mitchell ML, Hermos RJ, et al. Maternal thyroid deficiency and pregnancy complications: implications for population screening. J Med Screen 2000; 7(3):127-30.
  10. LeBeau SO, Mandel SJ. Thyroid disorders during pregnancy. Endocrinol Metab Clin North Am 2006; 35(1):117–36.
  11. Wang S, Teng WP, Li JX, Wang WW, Shan ZY. Effects of maternal subclinical hypothyroidism on obstetrical outcomes during early pregnancy. J Endocrinol Invest 2012; 35(3):322-5.
  12. Cleary-Goldman J, Malone FD, Lambert-Messerlian G, Sullivan L, Canick J, Porter TF, et al. Maternal thyroid hypofunction and pregnancy outcome. Obstet Gynecol 2008; 112(1):85-92.
  13. Korevaar TI, Schalekamp-Timmermans S, de Rijke YB, Visser WE, Visser W, de Muinck Keizer-Schrama SM, et al. Hypothyroxinemia and TPO-antibody positivity are risk factors for premature delivery: the generation R study. J Clin Endocrinol Metab 2013; 98(11):4382-90.
  14. Casey BM, Dashe JS, Wells CE, McIntire DD, Byrd W, Leveno KJ, et al. Subclinical hypothyroidism and pregnancy outcomes. Obstet Gynecol 2005; 105(2):239-45.
  15. Su PY, Huang K, Hao JH, Xu YQ, Yan SQ, Li T, 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):3234-41.
  16. Mannisto T, Vaarasmaki M, Pouta A, Hartikainen AL, Ruokonen A, Surcel HM, et al. Perinatal outcome of children born to mothers with thyroid dysfunction or antibodies: a prospective population-based cohort study. J Clin Endocrinol Metab 2009; 94(3):772-9.
  17. Ajmani SN, Aggarwal D, Bhatia P, Sharma M, Sarabhai V, Paul M. Prevalence of overt and subclinical thyroid dysfunction among pregnant women and its effect on maternal and fetal outcome. J Obstet Gynaecol India 2014; 64(2):105-10.
  18. Ong GS, Hadlow NC, Brown SJ, Lim EM, Walsh JP. Does the thyroid-stimulating hormone measured concurrently with first trimester biochemical screening tests predict adverse pregnancy outcomes occurring after 20 weeks gestation? J Clin Endocrinol Metab 2014; 99(12):E2668-72.
  19. Chen LM, Du WJ, Dai J, Zhang Q, Si GX, Yang H, et al. Effects of subclinical hypothyroidism on maternal and perinatal outcomes during pregnancy: a single-center cohort study of a Chinese population. PloS One 2014; 9(10):e109364.
  20. Lahoti SK, Toppo L. Subclinical hypothyroidism and pregnancy outcomes. Ann Int Med Den Res 2015; 1(3):324-26.
  21. Sahu MT, Das V, Mittal S, Agarwal A, Sahu M. Overt and subclinical thyroid dysfunction among Indian pregnant women and its effect on maternal and fetal outcome. Arch Gynecol Obstet 2010; 281(2):215-20.
  22. Saki F, Dabbaghmanesh MH, Ghaemi SZ, Forouhari S, Ranjbar Omrani G, Bakhshayeshkaram M. Thyroid function in pregnancy and its influences on maternal and fetal outcomes. Int J Endocrinol Metab 2014; 12(4):e19378.
    1. Nassie DI, Ashwal E, Raban O, Ben-Haroush A, Wiznitzer A, Yogev Y, et al. Is there an association between subclinical hypothyroidism and preterm uterine contractions? A prospective observational study. The Journal of Maternal-Fetal & Neonatal Medicine. 2016:1-5.
    2. Hadar E, Arbib N, Krispin E, Chen R, Wiznitzer A, et al. First trimester thyroid stimulating hormone as an independent risk factor for adverse pregnancy outcome. American Journal of Obstetrics & Gynecology 2017; 26(1): S435.
    3. Breathnach FM, Donnelly J, Cooley SM, Geary M, Malone FD. Subclinical hypothyroidism as a risk factor for placental abruption: Evidence from a low‐risk primigravid population. Australian and New Zealand Journal of Obstetrics and Gynaecology. 2013;53(6):553-60.
    4. Hamm MP, Cherry NM, Martin JW, Bamforth F, Burstyn I. The impact of isolatedmaternalhypothyroxinemia on perinatalmorbidity. J Obstet Gynaecol Can. 2009 Nov;31(11):1015-21.
    5. Nazarpour S, Ramezani Tehrani F, Simbar M, Azizi F. Pregnancy outcomes in pregnant women with hypothyroidism (a review article). Iran J Obstet Gynecol Infertil 2014; 17(126):17-26. (Persian).
    6. Spector TD, Thompson SG. The potential and limitations of meta-analysis. J Epidemiol Community Health 1991; 45(2):89-92.
    7. Sayehmiri K, Darvishi Z, Azami M, Qavam S. The prevalence of anemia in first, second and third trimester of pregnancy in Iran: a systematic review and meta-analysis. Iran J Obstet Gynecol Infertil 2015; 18:7-15. (Persian).
    8. Azami M, Khataee M, Bigam Bigdeli-Shamlo M, Abasalizadeh F, Abasalizadeh S, et al. Prevalence and risk factors of hepatitis B infection in pregnant women of Iran: a systematic review and meta-analysis. Iran J Obstet Gynecol Infertil 2016; 19(18):17-30. (Persian).
    9. Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ 2015; 349:g7647.
    10. Vandenbroucke JP, von Elm E, Altman DG, Gøtzsche PC, Mulrow CD, Pocock SJ, et al. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration. PLoS Med 2007; 4(10):e297.
    11. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7(3):177–88.
    12. Ades AE, Lu G, Higgins JP. The interpretation of random-effects meta-analysis in decision models. Med Decis Making 2005; 25(6):646-54.
    13. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327(7414):557–60.
    14. Stagnaro-Green A. Thyroid antibodies and miscarriage: where are we at a generation later? J Thyroid Res 2011; 2011:841949.
    15. Challis JR, Lockwood CJ, Myatt L, Norman JE, Strauss JF 3rd, Petraglia F. Inflammation and pregnancy. Reprod Sci 2009; 16(2):206–15.
    16. Hou J, Yu P, Zhu H, Pan H, Li N, Yang H, et al. The impact of maternal hypothyroidism during pregnancy on neonatal outcomes: a systematic review and meta-analysis. Gynecol Endocrinol 2016; 32(1):9-13.
    17. Sheehan PM, Nankervis A, Araujo Junior E, Da Silva Costa F. Maternal thyroid disease and preterm birth: systematic review and meta analysis. J Clin Endocrinol Metab 2015; 100(11):4325-31.