Abstract
Thyroid diseases are relatively common in women in the reproductive period. It is currently understood that clinically-evident thyroid disorders may impair ovulation and, consequently, fertility. However, to date it has not been proven that high serum levels of thyroid-stimulating hormone and/or positivity for antithyroid antibodies are associated to a reduction in fertility, mainly in the absence of altered thyroxine levels. The present comprehensive review aims to present current data on the association between subclinical hypothyroidism and/or thyroid autoimmunity and reproductive outcomes.
Keywords:
thyroid diseases; thyroid function tests; thyroid hormones; hypothyroidism; autoimmunity; female infertility
Resumo
As doenças da tireoide são relativamente comuns em mulheres no período reprodutivo. Atualmente, entende-se que distúrbios da tireoide clinicamente evidentes podem prejudicar a ovulação e, consequentemente, a fertilidade. No entanto, não se provou até o presente que níveis séricos altos do hormônio estimulador da tireoide e/ou positividade para anticorpos antitireoidianos estão associados a uma redução na fertilidade, sobretudo na ausência de níveis alterados de tiroxina. Esta revisão narrativa tem como objetivo apresentar dados atuais sobre a associação entre hipotireoidismo subclínico e/ou autoimunidade tireoidiana e resultados reprodutivos.
Palavras-chave:
doenças da tireoide; testes de função da tireoide; hormônios da tireoide; hipotireoidismo; autoimunidade; infertilidade feminina
Introduction
The thyroid gland is responsible for regulating several mechanisms of human physiology, which include the reproductive function. Thyroid hormones are involved in the modulation of the hypothalamic-pituitary-gonadal axis and, despite the lack of consistent scientific evidence, it is currently understood that clinically evident thyroid disorders may impair ovulation and, consequently, fertility.11 Gracia CR. Thyroid in Reproduction. Semin Reprod Med. 2016;34 (06):315-316. Doi: 10.1055/s-0036-1593490
https://doi.org/10.1055/s-0036-1593490...
Thyroid diseases are relatively common in women in the reproductive period. A significant association between clinical thyroid disorders and abnormalities of the reproductive system has been largely confirmed: both primary hyperthyroidism and hypothyroidism have been documented to produce variable degrees of gonadal dysfunction. Nevertheless, the impact of subclinical thyroid dysfunction and/or thyroid autoimmunity (TAI) on fertility and reproductive outcomes is not consensual, although they may be related to infertility and the risk of spontaneous pregnancy loss.11 Gracia CR. Thyroid in Reproduction. Semin Reprod Med. 2016;34 (06):315-316. Doi: 10.1055/s-0036-1593490
https://doi.org/10.1055/s-0036-1593490...
22 Alexander EK, Pearce EN, Brent GA, Brown RS, Chen H, Dosiou C, et al. 2017 Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid. 2017;27(03):315-389. Doi: 10.1089/thy.2016.0457
https://doi.org/10.1089/thy.2016.0457...
As a matter of course, subclinical hypothyroidism (SCH) has been defined as a level of thyroid stimulating hormone (TSH) going over the upper threshold of 4.5 mIU/L to 5.0 mIU/L in the setting of a normal level of free thyroxine (fT4).33 Practice Committee of the American Society for Reproductive Medicine. Subclinical hypothyroidism in the infertile female population: a guideline. Fertil Steril. 2015;104(03):545-553. Doi: 10.1016/j.fertnstert.2015.05.028
https://doi.org/10.1016/j.fertnstert.201...
Nonetheless, the limits commonly vary among studies, and it has been suggested that the upper cutoff for TSH should be set at 2.5 mIU/L, based on the observation that 95% of asymptomatic people have that level or even lower levels of TSH.44 BalochZ, CarayonP,Conte-DevolxB,Demers LM, Feldt-RasmussenU, Henry JF, et al; Guidelines Committee, National Academy of Clinical Biochemistry. Laboratory medicine practice guidelines. Laboratory support for the diagnosis andmonitoring of thyroid disease. Thyroid. 2003;13(01):3-126. Doi: 10.1089/105072503321086962
https://doi.org/10.1089/1050725033210869...
Regarding thyroid diseases, in addition to idiopathic changes in function, situations resulting from the presence of autoantibodies are quite common, such as Hashimoto thyroiditis and Graves disease. Currently, at least three anti-thyroid antibodies can be evaluated in human serum: the thyroid globulin antibody (TGAb), the thyroid peroxidase antibody (TPOAb), and the thyrotropin receptor antibody (TRAb). However, presenting anti-thyroid antibodies is not sufficient to develop autoimmune thyroid disease, which pathophysiology is not yet fully understood. Thus, the clinical relevance of presenting positive antibodies without an established disease is still questionable, including the influence on fertility.55 Caturegli P, De Remigis A, Rose NR. Hashimoto thyroiditis: clinical and diagnostic criteria. Autoimmun Rev. 2014;13(4-5):391-397. Doi: 10.1016/j.autrev.2014.01.007
https://doi.org/10.1016/j.autrev.2014.01...
The present narrative review aims to present the current data on the association between SCH and/or TAI and reproductive outcomes. Our objective is to help clinicians decide the medical approach to women attempting to conceive and presenting those conditions, based on hierarchized evidence. However, once the levels of evidence do not provide a definitive judgment about the quality of the studies included nor they constitute a final recommendation,66 Howick J, Chalmers I, Glasziou P, Greenhalgh T, Heneghan C, Liberati A, et al. The 2011 Oxford CEBM Evidence Levels of Evidence: introductory document [Internet]. 2011 [cited 2020 May 12]. Available from: https://www.cebm.net/2011/06/2011- oxford-cebm-levels-evidence-introductory-document/
https://www.cebm.net/2011/06/2011- oxfor...
clinicians may apply individualization as the main key for their critical appraisal in treatment decisions.
Methods
Using the keywords subclinical hypothyroidism, thyroid autoimmunity, and infertility, we searched for clinical trials, controlled clinical trials, meta-analyses, and randomized controlled trials on the following databases: PubMed, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, the Cochrane Gynecology and Fertility Group specialized register, and clinicaltrials.gov. No date or language restrictions were applied to the search. A total of 13 studies were primarily selected for this review.77 RaberW, Nowotny P, Vytiska-Binstorfer E, Vierhapper H. Thyroxine treatment modified in infertile women according to thyroxine- releasing hormone testing: 5 year follow-up of 283 women referred after exclusion of absolute causes of infertility. Hum Reprod. 2003;18(04):707-714. Doi: 10.1093/humrep/deg142
https://doi.org/10.1093/humrep/deg142...
88 Abdel Rahman AH, Aly Abbassy H, Abbassy AAE. Improved in vitro fertilization outcomes after treatment of subclinical hypothyroidismin infertile women. Endocr Pract. 2010;16(05):792-797. Doi: 10.4158/EP09365.OR
https://doi.org/10.4158/EP09365.OR...
99 van den Boogaard E, Vissenberg R, Land JA, van Wely M, van der Post JA, Goddijn M, et al. Significance of (sub)clinical thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy: a systematic review. Hum Reprod Update. 2011; 17(05):605-619. Doi: 10.1093/humupd/dmr024
https://doi.org/10.1093/humupd/dmr024...
1010 Kim CH, Ahn JW, Kang SP, Kim SH, Chae HD, Kang BM. Effect of levothyroxine treatment on in vitro fertilization and pregnancy outcome in infertile womenwith subclinical hypothyroidism undergoing in vitro fertilization/intracytoplasmic sperm injection. Fertil Steril.2011;95(05):1650-1654.Doi:10.1016/j.fertnstert.2010.12.004
https://doi.org/10.1016/j.fertnstert.201...
1111 Bartáková J, Potluková E, Rogalewicz V, Fait T, Schöndorfová D, Telicka Z, et al. Screening for autoimmune thyroid disorders after spontaneous abortion is cost-saving and it improves the subsequent pregnancy rate. BMC Pregnancy Childbirth. 2013;13:217. Doi: 10.1186/1471-2393-13-217
https://doi.org/10.1186/1471-2393-13-217...
1212 Plowden TC, Schisterman EF, Sjaarda LA, Zarek SM, Perkins NJ, Silver R, et al. Subclinical hypothyroidism and thyroid autoimmunity are not associated with fecundity, pregnancy loss, or live birth. J Clin Endocrinol Metab. 2016;101(06):2358-2365. Doi: 10.1210/jc.2016-1049
https://doi.org/10.1210/jc.2016-1049...
1313 Busnelli A, Paffoni A, Fedele L, Somigliana E. The impact of thyroid autoimmunity on IVF/ICSI outcome: a systematic review and meta-analysis. Hum Reprod Update. 2016;22(06):775-790. Doi: 10.1093/humupd/dmw019
https://doi.org/10.1093/humupd/dmw019...
1414 Wang H, Gao H, Chi H, Zeng L, Xiao W, Wang Y, et al. Effect of levothyroxine onmiscarriage amongwomen with normal thyroid function and thyroid autoimmunity undergoing in vitro fertilization and embryo transfer: a randomized clinical trial. JAMA. 2017; 318(22):2190-2198. Doi: 10.1001/jama.2017.18249
https://doi.org/10.1001/jama.2017.18249...
1515 Cai Y, Zhong L, Guan J, Guo RJ, Niu B, Ma YP, et al. Outcome of in vitro fertilization in women with subclinical hypothyroidism. Reprod Biol Endocrinol. 2017;15(01):39. Doi: 10.1186/s12958-017-0257-2
https://doi.org/10.1186/s12958-017-0257-...
1616 Li J, Shen J, Qin L. Effects of levothyroxine on pregnancy outcomes in women with thyroid dysfunction: a meta-analysis of randomized controlled trials. Altern Ther Health Med. 2017;23(02):49-581717 Rao M, Zeng Z, Zhao S, Tang L. Effect of levothyroxine supplementation on pregnancy outcomes in women with subclinical hypothyroidism and thyroid autoimmuneity undergoing in vitro fertilization/intracytoplasmic sperm injection: an updated meta-analysis of randomized controlled trials. Reprod Biol Endocrinol. 2018;16(01):92. Doi: 10.1186/s12958-018-0410-6
https://doi.org/10.1186/s12958-018-0410-...
1818 Akhtar MA, Agrawal R, Brown J, Sajjad Y, Craciunas L. Thyroxine replacement for subfertile women with euthyroid autoimmune thyroid disease or subclinical hypothyroidism. Cochrane Database Syst Rev. 2019;6(06):CD011009. Doi: 10.1002/14651858.CD011009.pub2
https://doi.org/10.1002/14651858.CD01100...
1919 Dong AC, Morgan J, Kane M, Stagnaro-Green A, Stephenson MD. Subclinical hypothyroidismand thyroid autoimmunity in recurrent pregnancy loss: a systematic reviewandmeta-analysis. Fertil Steril. 2020;113(03):587-600.e1. Doi: 10.1016/j.fertnstert.2019.11.003
https://doi.org/10.1016/j.fertnstert.201...
The references of the selected studies were also checked, and seven more relevant articles were included.2020 Thangaratinam S, Tan A, Knox E, Kilby MD, Franklyn J, Coomarasamy A. Association between thyroid autoantibodies and miscarriage and pretermbirth: meta-analysis of evidence. BMJ. 2011; 342:d2616. Doi: 10.1136/bmj.d2616
https://doi.org/10.1136/bmj.d2616...
2121 Vissenberg R, vandenBoogaardE,vanWelyM, vanderPost JA, Fliers E, Bisschop PH, et al. Treatment of thyroid disorders before conception and in early pregnancy: a systematic review. Hum Reprod Update. 2012;18(04):360-373. Doi: 10.1093/humupd/dms007
https://doi.org/10.1093/humupd/dms007...
2222 Velkeniers B, VanMeerhaeghe A, Poppe K, Unuane D, Tournaye H, Haentjens P. Levothyroxine treatment and pregnancy outcome in women with subclinical hypothyroidism undergoing assisted reproduction technologies: systematic review and meta-analysis of RCTs. Hum Reprod Update. 2013;19(03):251-258. Doi:10.1093/humupd/dms052
https://doi.org/10.1093/humupd/dms052...
2323 Reid SM, Middleton P, Cossich MC, Crowther CA, Bain E. Interventions for clinical and subclinical hypothyroidism pre-pregnancy and during pregnancy. Cochrane Database Syst Rev. 2013; (05):CD007752. Doi: 10.1002/14651858.CD007752.pub3
https://doi.org/10.1002/14651858.CD00775...
2424 Negro R, Schwartz A, Stagnaro-Green A. Impact of levothyroxine in miscarriage and preterm delivery rates in first trimester thyroid antibody positive women with TSH less than 2.5 mIU/L. J Clin Endocrinol Metab. 2016;101(10):3685-3690. Doi: 10.1210/jc.2016-1803
https://doi.org/10.1210/jc.2016-1803...
2525 Dhillon-Smith RK, Middleton LJ, Sunner KK, Cheed V, Baker K, Farrell-Carver S, et al. Levothyroxine in women with thyroid peroxidase antibodies before conception. N Engl J Med. 2019; 380(14):1316-1325. Doi: 10.1056/NEJMoa1812537
https://doi.org/10.1056/NEJMoa1812537...
2626 Rao M, Zeng Z, Zhou F, Wang H, Liu J, Wang R, et al. 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. 2019;25(03):344-361. Doi: 10.1093/humupd/dmz003
https://doi.org/10.1093/humupd/dmz003...
The evidence was hierarchized according to the Oxford Centre for Evidence-based Medicine's 2011 Levels of Evidence66 Howick J, Chalmers I, Glasziou P, Greenhalgh T, Heneghan C, Liberati A, et al. The 2011 Oxford CEBM Evidence Levels of Evidence: introductory document [Internet]. 2011 [cited 2020 May 12]. Available from: https://www.cebm.net/2011/06/2011- oxford-cebm-levels-evidence-introductory-document/
https://www.cebm.net/2011/06/2011- oxfor...
by the first author (BRC), and checked by the second author (APN); there were no discordances between them or between them and the other authors.
Subclinical Hypothyroidism
Subclinical hypothyroidism is a condition in which the level of TSH is elevated, but the level of fT4 is normal. It represents an early, mild thyroid failure, and affects up to 10% of the adult population.2727 Biondi B, Cappola AR, Cooper DS. Subclinical hypothyroidism: a review. JAMA. 2019;322(02):153-160.Doi:10.1001/jama.2019.9052
https://doi.org/10.1001/jama.2019.9052...
However, its clinical significance has not been consistently proven. Raber et al77 RaberW, Nowotny P, Vytiska-Binstorfer E, Vierhapper H. Thyroxine treatment modified in infertile women according to thyroxine- releasing hormone testing: 5 year follow-up of 283 women referred after exclusion of absolute causes of infertility. Hum Reprod. 2003;18(04):707-714. Doi: 10.1093/humrep/deg142
https://doi.org/10.1093/humrep/deg142...
followed 223 women for up to 5 years, and they observed lower conception rates among women who never achieved a basal TSH < 20 mUI/L with fT4 therapy, and, then, they suggested a negative effect of such findings on reproductive function (level 4). Moreover, the meta-analysis of two studies2121 Vissenberg R, vandenBoogaardE,vanWelyM, vanderPost JA, Fliers E, Bisschop PH, et al. Treatment of thyroid disorders before conception and in early pregnancy: a systematic review. Hum Reprod Update. 2012;18(04):360-373. Doi: 10.1093/humupd/dms007
https://doi.org/10.1093/humupd/dms007...
showed a significant decrease in the rates of miscarriage (relative risk [RR]: 0.18; 95%; 95% confidence interval [95%CI]: 0.08–0.39; p < 0.01) and preterm delivery (RR: 0.41; 95%CI: 0.24–0.68; p = 0.0005) in women with SCH treated with levothyroxine (LT4) (level 1). However, contrary to those authors, preconception TSH ≥ 2.5 mIU/L was not associated to time to biochemical pregnancy (odds ratio [OR]: 1.09; 95%CI: 0.90–1.31), pregnancy loss (RR: 1.15; 95%CI: 0.86–1.54) or live births (RR: 1.01, 95%CI: 0.89–1.14) among 1,193 women with normal fT4 (0.7 ng/dL to 1.85 ng/dL) and a history of either one or two previous pregnancy losses, even if they were positive for anti-thyroid antibodies (TGAb ≥ 115 IU/mL and/or TPOAb ≥ 35 IU/mL), and after adjusting for age and body mass index. The authors also attempted to determine a TSH cut-off affecting the continuation of pregnancy, but an additional analysis of both TSH tertiles and continuous TSH did not result in differences between women with TSH ≥ 2.5 mIU/L and those with TSH < 2.5 mIU/L (level 2).1212 Plowden TC, Schisterman EF, Sjaarda LA, Zarek SM, Perkins NJ, Silver R, et al. Subclinical hypothyroidism and thyroid autoimmunity are not associated with fecundity, pregnancy loss, or live birth. J Clin Endocrinol Metab. 2016;101(06):2358-2365. Doi: 10.1210/jc.2016-1049
https://doi.org/10.1210/jc.2016-1049...
There are some studies evaluating the effect of LT4 in women with subclinical hypothyrodism undergoing assisted reproductive treatments, like in vitro fertilization (IVF), with conflicting results.88 Abdel Rahman AH, Aly Abbassy H, Abbassy AAE. Improved in vitro fertilization outcomes after treatment of subclinical hypothyroidismin infertile women. Endocr Pract. 2010;16(05):792-797. Doi: 10.4158/EP09365.OR
https://doi.org/10.4158/EP09365.OR...
1010 Kim CH, Ahn JW, Kang SP, Kim SH, Chae HD, Kang BM. Effect of levothyroxine treatment on in vitro fertilization and pregnancy outcome in infertile womenwith subclinical hypothyroidism undergoing in vitro fertilization/intracytoplasmic sperm injection. Fertil Steril.2011;95(05):1650-1654.Doi:10.1016/j.fertnstert.2010.12.004
https://doi.org/10.1016/j.fertnstert.201...
1515 Cai Y, Zhong L, Guan J, Guo RJ, Niu B, Ma YP, et al. Outcome of in vitro fertilization in women with subclinical hypothyroidism. Reprod Biol Endocrinol. 2017;15(01):39. Doi: 10.1186/s12958-017-0257-2
https://doi.org/10.1186/s12958-017-0257-...
2222 Velkeniers B, VanMeerhaeghe A, Poppe K, Unuane D, Tournaye H, Haentjens P. Levothyroxine treatment and pregnancy outcome in women with subclinical hypothyroidism undergoing assisted reproduction technologies: systematic review and meta-analysis of RCTs. Hum Reprod Update. 2013;19(03):251-258. Doi:10.1093/humupd/dms052
https://doi.org/10.1093/humupd/dms052...
2626 Rao M, Zeng Z, Zhou F, Wang H, Liu J, Wang R, et al. 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. 2019;25(03):344-361. Doi: 10.1093/humupd/dmz003
https://doi.org/10.1093/humupd/dmz003...
According to Kim et al,1010 Kim CH, Ahn JW, Kang SP, Kim SH, Chae HD, Kang BM. Effect of levothyroxine treatment on in vitro fertilization and pregnancy outcome in infertile womenwith subclinical hypothyroidism undergoing in vitro fertilization/intracytoplasmic sperm injection. Fertil Steril.2011;95(05):1650-1654.Doi:10.1016/j.fertnstert.2010.12.004
https://doi.org/10.1016/j.fertnstert.201...
women with subclinical hypothyroidism undergoing assisted reproductive techniques presented with similar clinical pregnancy rates when compared with controls, despite the significant differences in the number of good-quality embryos, implantation rates, and live-birth rates (RR: 1.8; 95%CI: 1.0–3.25; p = 0.05; and RR: 2.13; 95%CI: 1.07–4.21; p = 0.03 respectively).1010 Kim CH, Ahn JW, Kang SP, Kim SH, Chae HD, Kang BM. Effect of levothyroxine treatment on in vitro fertilization and pregnancy outcome in infertile womenwith subclinical hypothyroidism undergoing in vitro fertilization/intracytoplasmic sperm injection. Fertil Steril.2011;95(05):1650-1654.Doi:10.1016/j.fertnstert.2010.12.004
https://doi.org/10.1016/j.fertnstert.201...
However, the miscarriage rate was significantly lower in the LT4 group (no miscarriages versus 33,3% in the control group; p = 0.021) (level 2). In another trial,88 Abdel Rahman AH, Aly Abbassy H, Abbassy AAE. Improved in vitro fertilization outcomes after treatment of subclinical hypothyroidismin infertile women. Endocr Pract. 2010;16(05):792-797. Doi: 10.4158/EP09365.OR
https://doi.org/10.4158/EP09365.OR...
LT4 or placebo were initiated one month before IVF and were maintained throughout pregnancy. The number of follicles punctured, mature oocytes, and the fertilization, pregnancy, and delivery rates were significantly higher in the treatment group. Moreover, the miscarriage rate was significantly lower in the intervention group (level 1).88 Abdel Rahman AH, Aly Abbassy H, Abbassy AAE. Improved in vitro fertilization outcomes after treatment of subclinical hypothyroidismin infertile women. Endocr Pract. 2010;16(05):792-797. Doi: 10.4158/EP09365.OR
https://doi.org/10.4158/EP09365.OR...
In a cohort study by Cai et al,1515 Cai Y, Zhong L, Guan J, Guo RJ, Niu B, Ma YP, et al. Outcome of in vitro fertilization in women with subclinical hypothyroidism. Reprod Biol Endocrinol. 2017;15(01):39. Doi: 10.1186/s12958-017-0257-2
https://doi.org/10.1186/s12958-017-0257-...
270 women with SCH supplemented with LT4 before IVF were compared with 200 age-matched euthyroid women who underwent classical IVF or intracytoplasmic sperm injection (ICSI). In total, 176 out of 270 women completed all pregnancy visits of the study, and were included in the final analysis. In the SCH treated with LT4 and euthyroid groups of women who underwent IVF in the same period, the overall rates of clinical pregnancy (44.31% versus 38.36%; p = 0.251 respectively) and miscarriage (10.3% versus 10.7%, p = 0.39 respectively) were similar (level 3).1515 Cai Y, Zhong L, Guan J, Guo RJ, Niu B, Ma YP, et al. Outcome of in vitro fertilization in women with subclinical hypothyroidism. Reprod Biol Endocrinol. 2017;15(01):39. Doi: 10.1186/s12958-017-0257-2
https://doi.org/10.1186/s12958-017-0257-...
Moreover, another study1212 Plowden TC, Schisterman EF, Sjaarda LA, Zarek SM, Perkins NJ, Silver R, et al. Subclinical hypothyroidism and thyroid autoimmunity are not associated with fecundity, pregnancy loss, or live birth. J Clin Endocrinol Metab. 2016;101(06):2358-2365. Doi: 10.1210/jc.2016-1049
https://doi.org/10.1210/jc.2016-1049...
demonstrated that the treatment with LT4 lead to the same rates of clinical pregnancy, miscarriage, and live births, which were independent of TSH levels, in women with SCH. There were no differences between the groups regarding the total number of oocytes retrieved and good-quality embryos (level 2).1212 Plowden TC, Schisterman EF, Sjaarda LA, Zarek SM, Perkins NJ, Silver R, et al. Subclinical hypothyroidism and thyroid autoimmunity are not associated with fecundity, pregnancy loss, or live birth. J Clin Endocrinol Metab. 2016;101(06):2358-2365. Doi: 10.1210/jc.2016-1049
https://doi.org/10.1210/jc.2016-1049...
To enhance the challenge, two recent meta-analysis have shown that LT4 supplementation in women with SCH can significantly reduce the risk of miscarriage after assisted reproductive technologies (ARTs) in almost 50% (RR: 0.51; 95%CI: 0.32–0.82), but not the rate of preterm birth (RR: 1.13; 95%CI: 0.65–1.96). In women with TAI, LT4 supplementation reduced the risks of pregnancy loss (RR: 0.61; 95%CI: 0.39–0.96; p = 0.03) and preterm birth (RR: 0.49; 95%CI: 0.30–0.79; p = 0.003) in naturally-conceived pregnancies, but not in pregnancies achieved by ARTs (level 1).1717 Rao M, Zeng Z, Zhao S, Tang L. Effect of levothyroxine supplementation on pregnancy outcomes in women with subclinical hypothyroidism and thyroid autoimmuneity undergoing in vitro fertilization/intracytoplasmic sperm injection: an updated meta-analysis of randomized controlled trials. Reprod Biol Endocrinol. 2018;16(01):92. Doi: 10.1186/s12958-018-0410-6
https://doi.org/10.1186/s12958-018-0410-...
These results support previous similarly-designed studies (level 1).1616 Li J, Shen J, Qin L. Effects of levothyroxine on pregnancy outcomes in women with thyroid dysfunction: a meta-analysis of randomized controlled trials. Altern Ther Health Med. 2017;23(02):49-582222 Velkeniers B, VanMeerhaeghe A, Poppe K, Unuane D, Tournaye H, Haentjens P. Levothyroxine treatment and pregnancy outcome in women with subclinical hypothyroidism undergoing assisted reproduction technologies: systematic review and meta-analysis of RCTs. Hum Reprod Update. 2013;19(03):251-258. Doi:10.1093/humupd/dms052
https://doi.org/10.1093/humupd/dms052...
As a matter of fact, the last Cochrane review2323 Reid SM, Middleton P, Cossich MC, Crowther CA, Bain E. Interventions for clinical and subclinical hypothyroidism pre-pregnancy and during pregnancy. Cochrane Database Syst Rev. 2013; (05):CD007752. Doi: 10.1002/14651858.CD007752.pub3
https://doi.org/10.1002/14651858.CD00775...
concluded that evidence is not sufficient to support the recommendation of one prepregnancy or mid-pregnancy intervention over another, in cases of SCH (level 1). Given that their findings were only based on two trials with a moderate risk of bias, and that new trials have been published after that, the conclusion of a reduction in preterm birth and a trend toward reduced miscarriage with the use of LT4 therapy should be taken with caution when deciding to treat euthyroid women. More recently, a Cochrane systematic review1818 Akhtar MA, Agrawal R, Brown J, Sajjad Y, Craciunas L. Thyroxine replacement for subfertile women with euthyroid autoimmune thyroid disease or subclinical hypothyroidism. Cochrane Database Syst Rev. 2019;6(06):CD011009. Doi: 10.1002/14651858.CD011009.pub2
https://doi.org/10.1002/14651858.CD01100...
evaluated the LT4 treatment in subfertile women with SCH undergoing ARTs. Only in one study involving 64 women with both subclinical hypothyroidism and positive or negative TPOAb, LT4 replacement provided an improvement in the rate of live births (RR: 2.13; 95%CI: 1.07–4.21), with similar miscarriage rates (RR: 0.11; 95%CI: 0.01–1.98) (level 1).1818 Akhtar MA, Agrawal R, Brown J, Sajjad Y, Craciunas L. Thyroxine replacement for subfertile women with euthyroid autoimmune thyroid disease or subclinical hypothyroidism. Cochrane Database Syst Rev. 2019;6(06):CD011009. Doi: 10.1002/14651858.CD011009.pub2
https://doi.org/10.1002/14651858.CD01100...
Nevertheless, the authors could not draw clear conclusions due to the low to very low quality of the evidence reported.
Finally, according to the American Society for Reproductive Medicine,33 Practice Committee of the American Society for Reproductive Medicine. Subclinical hypothyroidism in the infertile female population: a guideline. Fertil Steril. 2015;104(03):545-553. Doi: 10.1016/j.fertnstert.2015.05.028
https://doi.org/10.1016/j.fertnstert.201...
evidence that SCH (defined as TSH > 2.5 mIU/L with a normal level of fT4) affects fertility or induces miscarriages is insufficient. In the absence of specific recommendations for women attempting pregnancy, there is a suggestion to use pregnancy thresholds to minimize the potential risks associated with SCH. The American Thyroid Association22 Alexander EK, Pearce EN, Brent GA, Brown RS, Chen H, Dosiou C, et al. 2017 Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid. 2017;27(03):315-389. Doi: 10.1089/thy.2016.0457
https://doi.org/10.1089/thy.2016.0457...
has published recommendations on the thresholds; briefly, in the absence of TAI, LT4 replacement is recommended for women presenting with TSH > 10.0 mIU/L (strong recommendation, but based on low-quality evidence), and could be considered for those presenting with TSH ≥ 4.0 mIU/L and < 10.0 mIU/L (weak recommendation, also based on low-quality evidence).
Thyroid Autoimmunity
Thyroid autoimmunity seems to be relatively common among women of reproductive age, and it might be associated with subfertility and adverse pregnancy outcomes, like miscarriage, recurrent miscarriage and preterm birth. Although not consensual, the literature suggests that the administration of LT4 can improve reproductive outcomes in women with normal thyroid function and positive thyroid autoantibodies (level 1).99 van den Boogaard E, Vissenberg R, Land JA, van Wely M, van der Post JA, Goddijn M, et al. Significance of (sub)clinical thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy: a systematic review. Hum Reprod Update. 2011; 17(05):605-619. Doi: 10.1093/humupd/dmr024
https://doi.org/10.1093/humupd/dmr024...
2020 Thangaratinam S, Tan A, Knox E, Kilby MD, Franklyn J, Coomarasamy A. Association between thyroid autoantibodies and miscarriage and pretermbirth: meta-analysis of evidence. BMJ. 2011; 342:d2616. Doi: 10.1136/bmj.d2616
https://doi.org/10.1136/bmj.d2616...
2828 Garg MK, Mahalle N, Hari Kumar KVS. Laboratory evaluation of thyroid function: dilemmas and pitfalls. Med J DY Patil Univ. 2016;9(04):430-436
First of all, the association between TAI and impaired fertility is still to be proven. In the study by Plowden et al,1212 Plowden TC, Schisterman EF, Sjaarda LA, Zarek SM, Perkins NJ, Silver R, et al. Subclinical hypothyroidism and thyroid autoimmunity are not associated with fecundity, pregnancy loss, or live birth. J Clin Endocrinol Metab. 2016;101(06):2358-2365. Doi: 10.1210/jc.2016-1049
https://doi.org/10.1210/jc.2016-1049...
TAI (TGAb ≥ 115 IU/mL and/or TPOAb ≥ 35 IU/mL) was examined in relation to time to biochemical pregnancy, pregnancy loss, and live birth among women with normal fT4 with one or two previous pregnancy losses. The authors did not find a significant delay in pregnancy (OR: 1.11; 95%CI: 0.88–1.40), higher risk of pregnancy loss (RR: 0.90; 95%CI: 0.61–1.33) or impaired live birth rate in women with circulating anti-thyroid antibodies (RR: 1.04; 95%CI: 0.90–1.20), even after adjusting for age and body mass index (level 2).1212 Plowden TC, Schisterman EF, Sjaarda LA, Zarek SM, Perkins NJ, Silver R, et al. Subclinical hypothyroidism and thyroid autoimmunity are not associated with fecundity, pregnancy loss, or live birth. J Clin Endocrinol Metab. 2016;101(06):2358-2365. Doi: 10.1210/jc.2016-1049
https://doi.org/10.1210/jc.2016-1049...
Addiotnally, according to van den Boogaard et al,99 van den Boogaard E, Vissenberg R, Land JA, van Wely M, van der Post JA, Goddijn M, et al. Significance of (sub)clinical thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy: a systematic review. Hum Reprod Update. 2011; 17(05):605-619. Doi: 10.1093/humupd/dmr024
https://doi.org/10.1093/humupd/dmr024...
2929 van den Boogaard E, Vissenberg R, Land JA, vanWelyM, ven der Post JA, Goddijn M, et al. Significance of (sub)clinical thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy: a systematic review.HumReprodUpdate. 2016;22(04):532-533. Doi: 10.1093/humupd/dmw003
https://doi.org/10.1093/humupd/dmw003...
no association was found between TAI and the rates of clinical pregnancy after IVF in the meta-analysis of seven studies (OR: 0.71; 95%CI: 0.36–1.4). However, the same study found elevated odds for unexplained subfertility (OR: 1.47; 95%CI: 1.06–2.02; p = 0.02), miscarriage (OR: 3.73; 95%CI: 1.83–7.6; p = 0.0003), recurrent miscarriage (OR: 2.26; 95%CI: 1.46–73.5; p = 0.0003), and preterm delivery (OR: 1.93; 95%CI: 1.08–3.47; p = 0.03) among euthyroid women positive for thyroid autoantibodies (level 1).99 van den Boogaard E, Vissenberg R, Land JA, van Wely M, van der Post JA, Goddijn M, et al. Significance of (sub)clinical thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy: a systematic review. Hum Reprod Update. 2011; 17(05):605-619. Doi: 10.1093/humupd/dmr024
https://doi.org/10.1093/humupd/dmr024...
2929 van den Boogaard E, Vissenberg R, Land JA, vanWelyM, ven der Post JA, Goddijn M, et al. Significance of (sub)clinical thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy: a systematic review.HumReprodUpdate. 2016;22(04):532-533. Doi: 10.1093/humupd/dmw003
https://doi.org/10.1093/humupd/dmw003...
In the same sense, the meta-analysis2020 Thangaratinam S, Tan A, Knox E, Kilby MD, Franklyn J, Coomarasamy A. Association between thyroid autoantibodies and miscarriage and pretermbirth: meta-analysis of evidence. BMJ. 2011; 342:d2616. Doi: 10.1136/bmj.d2616
https://doi.org/10.1136/bmj.d2616...
of seven homogeneous cohort studies demonstrated a significant elevation in the odds of miscarriage among subfertile women presenting with thyroid autoantibodies (OR: 3.15; 95%CI: 2.23–4.44; p < 0.001), especially TPOAb, but such an association was not proven by analyzing the three eligible studies involving women with recurrent pregnancy loss. Moreover, the authors found a 2-fold increase in the odds of preterm birth in the presence of TAI (OR: 2.07; 95%CI: 1.17–3.68; p = 0.01), with a significant 52% reduction in the relative risk of miscarriage (RR: 0.48; 95%CI: 0.25- 0.92; p = 0.03) and a 69% reduction in the relative risk of preterm birth (RR: 0.31 95%CI: 0.11–0.9; p < 0.05) when LT4 was supplemented in women with thyroid autoantibodies (level 1).2020 Thangaratinam S, Tan A, Knox E, Kilby MD, Franklyn J, Coomarasamy A. Association between thyroid autoantibodies and miscarriage and pretermbirth: meta-analysis of evidence. BMJ. 2011; 342:d2616. Doi: 10.1136/bmj.d2616
https://doi.org/10.1136/bmj.d2616...
Finally, in a recent meta-analysis, Dong et al1919 Dong AC, Morgan J, Kane M, Stagnaro-Green A, Stephenson MD. Subclinical hypothyroidismand thyroid autoimmunity in recurrent pregnancy loss: a systematic reviewandmeta-analysis. Fertil Steril. 2020;113(03):587-600.e1. Doi: 10.1016/j.fertnstert.2019.11.003
https://doi.org/10.1016/j.fertnstert.201...
showed an association between TAI and recurrent pregnancy loss (OR: 1.94; 95%CI: 1.43–2,.4), but LT4 did not improve the pregnancy outcomes (level 1).1919 Dong AC, Morgan J, Kane M, Stagnaro-Green A, Stephenson MD. Subclinical hypothyroidismand thyroid autoimmunity in recurrent pregnancy loss: a systematic reviewandmeta-analysis. Fertil Steril. 2020;113(03):587-600.e1. Doi: 10.1016/j.fertnstert.2019.11.003
https://doi.org/10.1016/j.fertnstert.201...
Despite the aforementioned findings, Vissenberg et al2121 Vissenberg R, vandenBoogaardE,vanWelyM, vanderPost JA, Fliers E, Bisschop PH, et al. Treatment of thyroid disorders before conception and in early pregnancy: a systematic review. Hum Reprod Update. 2012;18(04):360-373. Doi: 10.1093/humupd/dms007
https://doi.org/10.1093/humupd/dms007...
could not demonstrate the benefits of treating euthyroid women with positive thyroid autoantibodies with LT4 (level 1).2121 Vissenberg R, vandenBoogaardE,vanWelyM, vanderPost JA, Fliers E, Bisschop PH, et al. Treatment of thyroid disorders before conception and in early pregnancy: a systematic review. Hum Reprod Update. 2012;18(04):360-373. Doi: 10.1093/humupd/dms007
https://doi.org/10.1093/humupd/dms007...
In a preview cohort study, Raber et al77 RaberW, Nowotny P, Vytiska-Binstorfer E, Vierhapper H. Thyroxine treatment modified in infertile women according to thyroxine- releasing hormone testing: 5 year follow-up of 283 women referred after exclusion of absolute causes of infertility. Hum Reprod. 2003;18(04):707-714. Doi: 10.1093/humrep/deg142
https://doi.org/10.1093/humrep/deg142...
did not find a significant association between the presence of TPOAb and TGAb and pregnancy or abortion rates in infertile women with or without SCH followed-up for more than 5 years (level 4). In accordance to those results, Dhillon-Smith et al2525 Dhillon-Smith RK, Middleton LJ, Sunner KK, Cheed V, Baker K, Farrell-Carver S, et al. Levothyroxine in women with thyroid peroxidase antibodies before conception. N Engl J Med. 2019; 380(14):1316-1325. Doi: 10.1056/NEJMoa1812537
https://doi.org/10.1056/NEJMoa1812537...
could not find significant differences in the rates of live births after at least 34 weeks of pregnancy by using 50 µg of LT4 once a day, started before conception and continued throughout pregnancy, among euthyroid women with TPOAb with a history of miscarriage or infertility. There was also no significant effect of LT4 on other pregnancy or neonatal outcomes, including the incidence of miscarriage and preterm birth (level 1).2525 Dhillon-Smith RK, Middleton LJ, Sunner KK, Cheed V, Baker K, Farrell-Carver S, et al. Levothyroxine in women with thyroid peroxidase antibodies before conception. N Engl J Med. 2019; 380(14):1316-1325. Doi: 10.1056/NEJMoa1812537
https://doi.org/10.1056/NEJMoa1812537...
Another trial1414 Wang H, Gao H, Chi H, Zeng L, Xiao W, Wang Y, et al. Effect of levothyroxine onmiscarriage amongwomen with normal thyroid function and thyroid autoimmunity undergoing in vitro fertilization and embryo transfer: a randomized clinical trial. JAMA. 2017; 318(22):2190-2198. Doi: 10.1001/jama.2017.18249
https://doi.org/10.1001/jama.2017.18249...
evaluated the treatment with LT4 initiated between 2 and 4 weeks before the controlled ovarian hyperstimulation for IVF and continued through the end of pregnancy in women with normal thyroid function who tested positive for TPOAb. The LT4 treatment did not reduce rates of miscarriage or improved the rates of live births compared with the usual care (level 1).1414 Wang H, Gao H, Chi H, Zeng L, Xiao W, Wang Y, et al. Effect of levothyroxine onmiscarriage amongwomen with normal thyroid function and thyroid autoimmunity undergoing in vitro fertilization and embryo transfer: a randomized clinical trial. JAMA. 2017; 318(22):2190-2198. Doi: 10.1001/jama.2017.18249
https://doi.org/10.1001/jama.2017.18249...
A recent Cochrane Systematic Review1818 Akhtar MA, Agrawal R, Brown J, Sajjad Y, Craciunas L. Thyroxine replacement for subfertile women with euthyroid autoimmune thyroid disease or subclinical hypothyroidism. Cochrane Database Syst Rev. 2019;6(06):CD011009. Doi: 10.1002/14651858.CD011009.pub2
https://doi.org/10.1002/14651858.CD01100...
also showed no differences in miscarriage rates or live-birth rates with the LT4 treatment or placebo in a similar group of women undergoing ARTs (level 1).
Beside all the lack of evidence to support the use of LT4 in euthyroid women with positive antibodies, Bartáková et al1111 Bartáková J, Potluková E, Rogalewicz V, Fait T, Schöndorfová D, Telicka Z, et al. Screening for autoimmune thyroid disorders after spontaneous abortion is cost-saving and it improves the subsequent pregnancy rate. BMC Pregnancy Childbirth. 2013;13:217. Doi: 10.1186/1471-2393-13-217
https://doi.org/10.1186/1471-2393-13-217...
analyzed the reproductive outcomes of 258 women up to 47 months after an episode of spontaneous abortion in the first trimester, and 43% of them were “positive for thyroid disorders” (level 3). Despite the fact that they found a significantly lower rate of secondary infertility among women treated with LT4 when compared with the controls and untreated women (4.1% versus 10.9% versus 21.1% respectively), such a finding was not clear when they compared the controls to treated and untreated positive women together (10.9% versus 9.9% respectively). The authors concluded that screening for thyroid disorders in women after spontaneous abortion and treatment with LT4 is cost-saving and improves the subsequent pregnancy rate.
In the absence of specific recommendations for women attempting pregnancy, some defend the use of pregnancy thresholds to minimize the potential risks associated with TAI. According to the most recent American Thyroid Association (ATA) recommendations,22 Alexander EK, Pearce EN, Brent GA, Brown RS, Chen H, Dosiou C, et al. 2017 Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid. 2017;27(03):315-389. Doi: 10.1089/thy.2016.0457
https://doi.org/10.1089/thy.2016.0457...
pregnant women presenting with TSH > 2.5 mIU/L should be regularly evaluated for TPOAb; briefly, for those TPOAb-positive, LT4 therapy is recommended if TSH ≥ 4.0 mIU/L (strong recommendation, based on moderate-quality evidence), and could be considered for those presenting with TSH > 2.5 mIU/L and < 4.0 mIU/L (weak recommendation, also based on moderate-quality evidence).
Practical Aspects
In the absence of sufficiently consistent scientific evidence on the approach of thyroid function in women attempting to conceive, and considering the aforementioned findings, we propose the following practical aspects:
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Healthy women actively attempting to conceive should not be evaluated for thyroid disorders (strong recommendation, evidence of moderate quality);1212 Plowden TC, Schisterman EF, Sjaarda LA, Zarek SM, Perkins NJ, Silver R, et al. Subclinical hypothyroidism and thyroid autoimmunity are not associated with fecundity, pregnancy loss, or live birth. J Clin Endocrinol Metab. 2016;101(06):2358-2365. Doi: 10.1210/jc.2016-1049
https://doi.org/10.1210/jc.2016-1049... -
Infertile women should be evaluated for thyroid disorders33 Practice Committee of the American Society for Reproductive Medicine. Subclinical hypothyroidism in the infertile female population: a guideline. Fertil Steril. 2015;104(03):545-553. Doi: 10.1016/j.fertnstert.2015.05.028
https://doi.org/10.1016/j.fertnstert.201... -
In infertile women presenting with TSH > 2.5 mIU/L, evaluate the TPOAb:
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(a) The LT4 therapy is recommended (strong recommendation, evidence of low to moderate quality) for women presenting:
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TPOAb-positive, TSH ≥ 4.0 mIU/L;
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TPOAb-negative, TSH > 10.0 mIU/L;
-
-
(b) The LT4 therapy may be individually considered (weak recommendation, evidence of moderate quality) for women presenting:
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TPOAb-positive, TSH > 2.5 mIU/L and < 4.0 mIU/L;
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TPOAb-negative, TSH ≥ 4.0 mIU/L and < 10.0 mIU/L;22 Alexander EK, Pearce EN, Brent GA, Brown RS, Chen H, Dosiou C, et al. 2017 Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid. 2017;27(03):315-389. Doi: 10.1089/thy.2016.0457
https://doi.org/10.1089/thy.2016.0457...
-
-
-
The LT4 therapy is not recommended (strong recommendation, evidence of high quality) for women presenting:
-
(a) TSH ≤ 2.5 mIU/mL;
-
(b) TPOAb-negative, TSH < 4.0 mIU/L.22 Alexander EK, Pearce EN, Brent GA, Brown RS, Chen H, Dosiou C, et al. 2017 Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid. 2017;27(03):315-389. Doi: 10.1089/thy.2016.0457
https://doi.org/10.1089/thy.2016.0457...
-
Laboratorial Pitfalls
Thyroid function tests (TFTs) are routinely ordered, but the evaluation and interpretation of the results may be difficult at times due to technical problems. The pitfalls in the hormonal evaluation can be preanalytical, analytical, and postanalytical. The preanalytical factors include age, pregnancy, use of medications (such as oral contraceptives and biotin), genetic mutations, systemic diseases, and critical illnesses. The analytical errors occur due to heterophile antibodies and macro-TSH. The postanalytical errors include wrong registration of the result by the laboratory, mistakes in the units of the parameter checked, and failure to identify the normal data.2828 Garg MK, Mahalle N, Hari Kumar KVS. Laboratory evaluation of thyroid function: dilemmas and pitfalls. Med J DY Patil Univ. 2016;9(04):430-4363030 Vandendriessche B, Lapauw B, Kaufman JM, Fiers T. A practical approach towards the evaluation of aberrant thyroid function tests. Acta Clin Belg. 2020;75(02):155-162. Doi: 10.1080/17843286.2019.1577531
https://doi.org/10.1080/17843286.2019.15...
Thus, before taking clinical decisions, it is important that the physician become aware of those challenges and repeat the test in case of doubt.
Final Considerations
The decision to treat SCH, particularly in women attempting pregnancy and infertile women, remains controversial, since the current understanding of the effect of thyroid dysfunction and/or autoimmunity on reproductive outcomes is based largely on low quality evidence. For this reason, the findings on the reproductive influence of SCH and TAI should be considered with care. Also because of the lacking evidence, the treatment with LT4 should not be established as a routine for women with SCH or those positive for thyroid autoantibodies as isolated findings, even assuming that potential benefits may outweigh the potential risks. As a matter of fact, the use LT4 will certainly benefit pregnant women with clinical hypothyroidism, and is an accepted strategy for those with a combination of TAI and elevated TSH. The treatment may be extended with caution and informed consent when that combination is found in subfertile women or those attempting pregnancy, but future better-designed studies are expected to support strong recommendations. Finally, screening for thyroid dysfunctions may be considered reasonable in women who are attempting to conceive and in the initial stage of pregnancy, but this is not consensual. Regarding the treatment with LT4, it is well established only in cases of clinical hypothyroidism, but it should be accepted in the following situations: 1) SCH associated to infertility; 2) TAI with TSH ≥ 4.0 mIU/L; or 3) when TSH > 10.0 mIU/L. Therefore, it should not be a rule for subclinical conditions, especially in the absence of autoimmunity. In the case of an individualized treatment for those who are candidates for maternity, we suggest that the same guidelines provided for pregnancy should be followed.
References
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» https://doi.org/10.1186/1471-2393-13-217 -
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» https://doi.org/10.1002/14651858.CD011009.pub2 -
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» https://doi.org/10.1016/j.fertnstert.2019.11.003 -
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» https://doi.org/10.1136/bmj.d2616 -
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» https://doi.org/10.1056/NEJMoa1812537 -
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28Garg MK, Mahalle N, Hari Kumar KVS. Laboratory evaluation of thyroid function: dilemmas and pitfalls. Med J DY Patil Univ. 2016;9(04):430-436
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29van den Boogaard E, Vissenberg R, Land JA, vanWelyM, ven der Post JA, Goddijn M, et al. Significance of (sub)clinical thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy: a systematic review.HumReprodUpdate. 2016;22(04):532-533. Doi: 10.1093/humupd/dmw003
» https://doi.org/10.1093/humupd/dmw003 -
30Vandendriessche B, Lapauw B, Kaufman JM, Fiers T. A practical approach towards the evaluation of aberrant thyroid function tests. Acta Clin Belg. 2020;75(02):155-162. Doi: 10.1080/17843286.2019.1577531
» https://doi.org/10.1080/17843286.2019.1577531
Publication Dates
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Publication in this collection
11 Jan 2021 -
Date of issue
Dec 2020
History
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Received
19 May 2020 -
Accepted
03 June 2020