The impact of mild subclinical hypothyroidism on pregnancy outcomes in TPOAb-negative women is poorly explored. The aim of the present study was the evaluation in a wide cohort of TPOAb-negative pregnant women the role of subclinical hypothyroidism (SCH) on several pregnancy outcomes.
The study included women aged ≥ 18 years with a singleton pregnancy without known thyroid disease with serum TSH concentration between 0.4 and 10 mIU/L and TPOAb negative. Data about clinical and demographic features were collected. A blood sample was drown to test TSH, TPOAb, ANA and ENA concentration. The mean uterine artery pulsatility index was measured. Risk of adverse obstetric and fetal outcomes was collected.
The cohort included 2135 pregnant women. Pregnant women with TSH 4–10 mUI/L had a significantly higher frequency of family history of thyroid diseases, and personal history of celiac disease diseases, type 1 diabetes mellitus, rheumatic disease, antinuclear antibody (ANA) and anti-extractable nuclear antigen (ENA) positive tests. The risk for pre-eclampsia and small for gestational age (SGA) was significantly higher in pregnant women with first-trimester TSH 4–10 mIU/L. A first-trimester TSH serum level greater than 4 mIU/L was associated with a significant increase in the occurrence of abnormal uterine artery pulsatility index, with a more than threefold increase in the risk of developing pre-eclampsia and with the risk of SGA.
In TPOAb-negative pregnant women, a first-trimester serum TSH level ranging from 4 to 10 mIU/L is significantly and independently linked to an increased uterine artery pulsatility index as well as to negative pregnancy outcomes such as pre-eclampsia, SGA and gestational diabetes.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price excludes VAT (USA)
Tax calculation will be finalised during checkout.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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) Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid 27(3):315–389. https://doi.org/10.1089/thy.2016.0457
Rotondi M, Chiovato L, Pacini F, Bartalena L, Vitti P (2018) Management of subclinical hypothyroidism in pregnancy: a comment from the Italian Society of Endocrinology and the Italian Thyroid Association to the 2017 American Thyroid Association Guidelines—"The Italian Way". Thyroid 28(5):551–555. https://doi.org/10.1089/thy.2017.0424
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):76–94. https://doi.org/10.1159/000362597
Leung AS, Millar LK, Koonings PP, Montoro M, Mestman JH (1993) Perinatal outcome in hypothyroid pregnancies. Obstet Gynecol 81(3):349–353
Idris I, Srinivasan R, Simm A, Page RC (2005) Maternal hypothyroidism in early and late gestation: effects on neonatal and obstetric outcome. Clin Endocrinol (Oxf) 63(5):560–565. https://doi.org/10.1111/j.1365-2265.2005.02382.x
Liu H, Shan Z, Li C, Mao J, Xie X, Wang W, Fan C, Wang H, Zhang H, Han C, Wang X, Liu X, Fan Y, Bao S, Teng W (2014) Maternal subclinical hypothyroidism, thyroid autoimmunity, and the risk of miscarriage: a prospective cohort study. Thyroid 24(11):1642–1649. https://doi.org/10.1089/thy.2014.0029
Benhadi N, Wiersinga WM, Reitsma JB, Vrijkotte TG, Bonsel GJ (2009) Higher maternal TSH levels in pregnancy are associated with increased risk for miscarriage, fetal or neonatal death. Eur J Endocrinol 160(6):985–991. https://doi.org/10.1530/EJE-08-0953
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 25 and 50 in the first trimester of pregnancy. J Clin Endocrinol Metab 95(9):E44–E48. https://doi.org/10.1210/jc.2010-0340
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. https://doi.org/10.1210/jc.2013-2855
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 Pregnancy and Postpartum (2011) Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 21(10):1081–1125. https://doi.org/10.1089/thy.2011.0087
Lee SY, Cabral HJ, Aschengrau A, Pearce EN (2020) Associations between maternal thyroid function in pregnancy and obstetric and perinatal outcomes. J Clin Endocrinol Metab 105(5):e2015–e2023. https://doi.org/10.1210/clinem/dgz275
Sheehan PM, Nankervis A, Araujo Júnior E, Da Silva CF (2015) Maternal thyroid disease and preterm birth: systematic review and meta-analysis. J Clin Endocrinol Metab 100(11):4325–4331. https://doi.org/10.1210/jc.2015-3074
Männistö T, Vääräsmäki M, Pouta A, Hartikainen AL, Ruokonen A, Surcel HM, Bloigu A, Järvelin MR, Suvanto-Luukkonen E (2009) Perinatal outcome of children born to mothers with thyroid dysfunction or antibodies: a prospective population-based cohort study. J Clin Endocrinol Metab 94(3):772–779. https://doi.org/10.1210/jc.2008-1520
Consortium on Thyroid and Pregnancy—Study Group on Preterm Birth, Korevaar TIM, Derakhshan A, Taylor PN, Meima M, Chen L, Bliddal S, Carty DM, Meems M, Vaidya B, Shields B, Ghafoor F, Popova PV, Mosso L, Oken E, Suvanto E, Hisada A, Yoshinaga J, Brown SJ, Bassols J, Auvinen J, Bramer WM, López-Bermejo A, Dayan C, Boucai L, Vafeiadi M, Grineva EN, Tkachuck AS, Pop VJM, Vrijkotte TG, Guxens M, Chatzi L, Sunyer J, Jiménez-Zabala A, Riaño I, Murcia M, Lu X, Mukhtar S, Delles C, Feldt-Rasmussen U, Nelson SM, Alexander EK, Chaker L, Männistö T, Walsh JP, Pearce EN, Steegers EAP, Peeters RP (2019) Association of thyroid function test abnormalities and thyroid autoimmunity with preterm birth: a systematic review and meta-analysis. JAMA 322(7):632–641. https://doi.org/10.1001/jama.2019.10931
Beneventi F, De Maggio I, Bellingeri C, Cavagnoli C, Spada C, Boschetti A, Magri F, Spinillo A (2022) Thyroid autoimmunity and adverse pregnancy outcomes: a prospective cohort study. Endocrine 76(1):198–207. https://doi.org/10.1007/s12020-021-02958-w
Pearce EN, Oken E, Gillman MW, Lee SL, Magnani B, Platek D, Braverman LE (2008) Association of first-trimester thyroid function test values with thyroperoxidase antibody status, smoking, and multivitamin use. Endocr Pract 14(1):33–39. https://doi.org/10.4158/EP.14.1.33
Blatt AJ, Nakamoto JM, Kaufman HW (2012) National status of testing for hypothyroidism during pregnancy and postpartum. J Clin Endocrinol Metab 97(3):777–784. https://doi.org/10.1210/jc.2011-2038
Negro R, Formoso G, Mangieri T, Pezzarossa A, Dazzi D, Hassan H (2006) Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: effects on obstetrical complications. J Clin Endocrinol Metab 91(7):2587–2591. https://doi.org/10.1210/jc.2005-1603
Thangaratinam S, Tan A, Knox E, Kilby MD, Franklyn J, Coomarasamy A (2011) Association between thyroid autoantibodies and miscarriage and preterm birth: meta-analysis of evidence. BMJ 9(342):d2616. https://doi.org/10.1136/bmj.d2616
Glinoer D, Riahi M, Grün JP, Kinthaert J (1994) Risk of subclinical hypothyroidism in pregnant women with asymptomatic autoimmune thyroid disorders. J Clin Endocrinol Metab 79(1):197–204. https://doi.org/10.1210/jcem.79.1.8027226
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):455–464. https://doi.org/10.1530/EJE-12-0379
De Leo S, Pearce EN (2018) Autoimmune thyroid disease during pregnancy. Lancet Diabetes Endocrinol 6(7):575–586. https://doi.org/10.1016/S2213-8587(17)30402-3
Zhu P, Chu R, Pan S, Lai X, Ran J, Li X (2021) Impact of TPOAb-negative maternal subclinical hypothyroidism in early pregnancy on adverse pregnancy outcomes. Ther Adv Endocrinol Metab. https://doi.org/10.1177/20420188211054690
Chen J, Zhu J, Huang X, Zhao S, Xiang H, Zhou P, Zhou T, Xu Z (2022) Subclinical hypothyroidism with negative for thyroid peroxidase antibodies in pregnancy: intellectual development of offspring. Thyroid 32(4):449–458. https://doi.org/10.1089/thy.2021.0374
Plowden TC, Schisterman EF, Sjaarda LA, Perkins NJ, Silver R, Radin R, Kim K, Galai N, DeCherney AH, Mumford SL (2017) Thyroid-stimulating hormone, anti-thyroid antibodies, and pregnancy outcomes. Am J Obstet Gynecol 217(6):697.e1-697.e7. https://doi.org/10.1016/j.ajog.2017.09.001
Spinillo A, Beneventi F, Ramoni V, Caporali R, Locatelli E, Simonetta M, Cavagnoli C, Alpini C, Albonico G, Prisco E, Montecucco C (2012) Prevalence and significance of previously undiagnosed rheumatic diseases in pregnancy. Ann Rheum Dis 71(6):918–923. https://doi.org/10.1136/annrheumdis-2011-154146
Bhide A, Acharya G, Bilardo CM, Brezinka C, Cafici D, Hernandez-Andrade E, Kalache K, Kingdom J, Kiserud T, Lee W, Lees C, Leung KY, Malinger G, Mari G, Prefumo F, Sepulveda W, Trudinger B (2013) ISUOG practice guidelines: use of Doppler ultrasonography in obstetrics. Ultrasound Obstet Gynecol 41(2):233–239. https://doi.org/10.1002/uog.12371
Frusca T, Soregaroli M, Valcamonico A, Guandalini F, Danti L (1997) Doppler velocimetry of the uterine arteries in nulliparous women. Early Hum Dev 48(1–2):177–185. https://doi.org/10.1016/s0378-3782(96)01854-3
Drukker L, Staines-Urias E, Villar J, Barros FC, Carvalho M, Munim S, McGready R, Nosten F, Berkley JA, Norris SA, Uauy R, Kennedy SH, Papageorghiou AT (2020) International gestational age-specific centiles for umbilical artery Doppler indices: a longitudinal prospective cohort study of the INTERGROWTH-21st Project. Am J Obstet Gynecol 222(6):602.e1-602.e15. https://doi.org/10.1016/j.ajog.2020.01.012
Lees CC, Stampalija T, Baschat A, da Silva CF, Ferrazzi E, Figueras F, Hecher K, Kingdom J, Poon LC, Salomon LJ, Unterscheider J (2020) ISUOG practice guidelines: diagnosis and management of small-for-gestational-age fetus and fetal growth restriction. Ultrasound Obstet Gynecol 56(2):298–312. https://doi.org/10.1002/uog.22134
ACOG Practice Bulletin No. 202 (2019) Gestational hypertension and preeclampsia. Obstet Gynecol 133(1):1. https://doi.org/10.1097/AOG.0000000000003018
Bertino E, Spada E, Occhi L, Coscia A, Giuliani F, Gagliardi L, Gilli G, Bona G, Fabris C, De Curtis M, Milani S (2010) Neonatal anthropometric charts: the Italian neonatal study compared with other European studies. J Pediatr Gastroenterol Nutr 51(3):353–361. https://doi.org/10.1097/MPG.0b013e3181da213e
Rolnik DL, Wright D, Poon LCY, Syngelaki A, O’Gorman N, de Paco MC, Akolekar R, Cicero S, Janga D, Singh M, Molina FS, Persico N, Jani JC, Plasencia W, Papaioannou G, Tenenbaum-Gavish K, Nicolaides KH (2017) ASPRE trial: performance of screening for preterm pre-eclampsia. Ultrasound Obstet Gynecol 50(4):492–495. https://doi.org/10.1002/uog.18816
Guttmacher AE, Maddox YT, Spong CY (2014) The Human Placenta Project: placental structure, development, and function in real time. Placenta 35(5):303–304. https://doi.org/10.1016/j.placenta.2014.02.012
Cartwright JE, Fraser R, Leslie K, Wallace AE, James JL (2010) Remodelling at the maternal-fetal interface: relevance to human pregnancy disorders. Reproduction 140(6):803–813. https://doi.org/10.1530/REP-10-0294
Vasilopoulou E, Loubière LS, Lash GE, Ohizua O, McCabe CJ, Franklyn JA, Kilby MD, Chan SY (2014) Triiodothyronine regulates angiogenic growth factor and cytokine secretion by isolated human decidual cells in a cell-type specific and gestational age-dependent manner. Hum Reprod 29(6):1161–1172. https://doi.org/10.1093/humrep/deu046
Wu MQ, Liu J, Wang YQ, Yang Y, Yan CH, Hua J (2019) The impact of subclinical hypothyroidism on adverse perinatal outcomes and the role of thyroid screening in pregnancy. Front Endocrinol (Lausanne) 6(10):522. https://doi.org/10.3389/fendo.2019.00522
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):e109364. https://doi.org/10.1371/journal.pone.0109364
Yuan N, Sun J, Zhao X, Du J, Nan M, Zhang Q, Zhang X (2022) Untreated thyroid autoantibody-negative SCH increases the risk of spontaneous abortions. Endocr Connect 11(4):e210600. https://doi.org/10.1530/EC-21-0600
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. https://doi.org/10.1210/jc.2011-2803
Azizi F, Amouzegar A (2011) Management of hyperthyroidism during pregnancy and lactation. Eur J Endocrinol 164(6):871–876. https://doi.org/10.1530/EJE-10-1030
Monen L, Kuppens SM, Hasaart TH, Oosterbaan HP, Oei SG, Wijnen H, Hutton EK, Vader HL, Pop VJ (2015) Maternal thyrotropin is independently related to small for gestational age neonates at term. Clin Endocrinol (Oxf) 82(2):254–259. https://doi.org/10.1111/cen.12578
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):580–590. https://doi.org/10.1089/thy.2015.0418
Amouzegar A, Pearce EN, Mehran L, Lazarus J, Takyar M, Azizi F (2022) TPO antibody in euthyroid pregnant women and cognitive ability in the offspring: a focused review. J Endocrinol Invest 45(2):425–431. https://doi.org/10.1007/s40618-021-01664-8
McCowan L, Horgan RP (2009) Risk factors for small for gestational age infants. Best Pract Res Clin Obstet Gynaecol 23(6):779–793. https://doi.org/10.1016/j.bpobgyn.2009.06.003
Campbell MK, Cartier S, Xie B, Kouniakis G, Huang W, Han V (2012) Determinants of small for gestational age birth at term. Paediatr Perinat Epidemiol 26(6):525–533. https://doi.org/10.1111/j.1365-3016.2012.01319.x
Derakhshan A, Peeters RP, Taylor PN et al (2020) Association of maternal thyroid function with birthweight: a systematic review and individual-participant data meta-analysis. Lancet Diabetes Endocrinol 8(6):501–510. https://doi.org/10.1016/S2213-8587(20)30061-9
Amiri M, Nazarpour S, Ramezani Tehrani F, Sheidaei A, Azizi F (2022) The targeted high-risk case-finding approach versus universal screening for thyroid dysfunction during pregnancy: thyroid-stimulating hormone (TSH) and/or thyroid peroxidase antibody (TPOAb) test? J Endocrinol Investig 45(9):1641–1651. https://doi.org/10.1007/s40618-021-01738-7
Peng CC, Pearce EN (2022) An update on thyroid disorders in the postpartum period. J Endocrinol Investig 45(8):1497–1506. https://doi.org/10.1007/s40618-022-01762-1
Elfström P, Montgomery SM, Kämpe O, Ekbom A, Ludvigsson JF (2008) Risk of thyroid disease in individuals with celiac disease. J Clin Endocrinol Metab 93(10):3915–3921. https://doi.org/10.1210/jc.2008-0798
Betterle C, Lazzarotto F, Presotto F (2004) Autoimmune polyglandular syndrome Type 2: the tip of an iceberg? Clin Exp Immunol 137(2):225–233. https://doi.org/10.1111/j.1365-2249.2004.02561.x
Molitch ME, Gillam MP (2007) Lymphocytic hypophysitis. Horm Res 68(Suppl 5):145–150. https://doi.org/10.1159/000110611
Rotondi M, Cappelli C, Leporati P, Chytiris S, Zerbini F, Fonte R, Magri F, Castellano M, Chiovato L (2010) A hypoechoic pattern of the thyroid at ultrasound does not indicate autoimmune thyroid diseases in patients with morbid obesity. Eur J Endocrinol 163(1):105–109. https://doi.org/10.1530/EJE-10-0288
Ekinci EI, Chiu WL, Lu ZX, Sikaris K, Churilov L, Bittar I, Lam Q, Crinis N, Houlihan CA (2015) A longitudinal study of thyroid autoantibodies in pregnancy: the importance of test timing. Clin Endocrinol (Oxf) 82(4):604–610. https://doi.org/10.1111/cen.12571
This paper was not supported by any grant or funding.
Conflict of interest
Flavia Magri, Laura Croce, Luca Chiovato and Mario Rotondi are members of the Editorial Board of Journal of Endocrinological Investigation. On behalf of the other authors, the corresponding author states that there is no conflict of interest.
This research was performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. This study, involving human participants, was approved by the appropriate institutional research ethics committee (IRCCS Policlinico San Matteo Foundation Ethical Committee -901-rcr2017i-23).
Informed consent was obtained from all the individual participants.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Below is the link to the electronic supplementary material.
About this article
Cite this article
Magri, F., Bellingeri, C., De Maggio, I. et al. A first-trimester serum TSH in the 4–10 mIU/L range is associated with obstetric complications in thyroid peroxidase antibody-negative women. J Endocrinol Invest 46, 1407–1414 (2023). https://doi.org/10.1007/s40618-022-01996-z