Evidence on the treatment of euthyroid infertile women and thyroid autoimmunity with thyroid hormone is scare, and therefore the recent study by Wang et al. is a welcome addition to it. Based on their results, thyroid hormone seems not to be indicated to decrease the miscarriage rate in that particular group of infertile women. This comment is meant to put the study results into perspective with the available evidence and the current guidelines, and to highlight its strengths and weaknesses. Keywords: ART, ICSI, IVF, Infertility, Miscarriage, Pregnancy outcome, Thyroid function and autoimmunity Background creates a less favourable environment, impairing the Thyroid autoimmunity (TAI), defined by the presence of in- in-vitro embryo development and/or the early phase of im- creased levels of anti-thyroid peroxidase antibodies plantation . Taking into consideration the latter hypoth- (TPO-abs) and/or anti-thyroglobulin antibodies (Tg-abs) is esis, a research question is whether thyroid hormone a frequent finding in the general population (~ 10% de- treatment (LT4) could overcome this relative thyroid dys- pending on the iodine intake of the investigated popula- function caused by TAI? tion), and is even higher in infertile women with polycystic ovaries and idiopathic infertility (~ 20–30%) [1, 2]. Women Main text with TAI and treated with ovarian hyperstimulation as In this randomized clinical trial, treatment with LT4 in preparation of an assisted reproductivetechnology(ART) euthyroid infertile women with TAI and treated with have a more important (and often definitive) decrease in ART (IVF (in-vitro fertilization) or ICSI (intra-cytoplas- their thyroid hormone levels compared with women with- mic sperm injection)) did not reduce the miscarriage out TAI . Finally, the presence of TAI is associated with rate before 28 weeks’ gestation compared with placebo an increased risk of a first trimester miscarriage, and a (10.3% versus 10.6%) . number of reasons for that association have been proposed Strengths of the study were the large number of patients [4, 5]. Compared with women without TAI, women with included (all with TPO-abs), and the exclusion of women TAI are older, have more often concomitant autoimmune with other auto-immune antibodies, such as anticardioli- disorders (reflected by the presence of anticardiolipin, anti- pin, antinuclear and lupus anticoagulants. Women in both nuclear, or lupus anticoagulants), may have an immune im- study groups received the same ovarian stimulation proto- balance of which thyroid antibodies are markers, and finally cols, and the number of (fresh) embryos transferred was do they have mild thyroid hypofunction that subsequently comparable. Finally, the initiation of LT4 before the ovar- ian stimulation procedure (i.e. before pregnancy) and the * Correspondence: email@example.com titration of the LT4 dosage during pregnancy to obtain Endocrine Unit Centre Hospitalier Universitaire Saint Pierre, Rue Haute 322, TSH levels within trimester-specific reference ranges were 1000 Brussels, Belgium 3 additional strengths and an amelioration compared with Université Libre de Bruxelles (ULB), 1050 Brussels, Belgium Full list of author information is available at the end of the article previous studies in the field . © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Poppe et al. Thyroid Research (2018) 11:7 Page 2 of 3 Before the study by Wang et al., evidence on LT4 treat- level within the upper limit of the assay (often < 4 to 5 ment in infertile women with TAI was limited to a few mIU/L), while for the period 2010–2016, it was < 2.5 studies with negative outcomes, however, these studies mIU/L [10, 13]. The lower upper limit in the more recent were subject to a number of important limitations [8, 9]. studies might be a reason why the presence of TAI was In the study by Negro et al., a non-significant difference in not anymore associated with altered ART outcomes, as it the miscarriage rate was noted (in favour of the LT4 was shown in a number of recent studies [14–16]. group), but it was underpowered and subject to a type II ICSI and LT4 treatments can also be complementary statistical error . The study by Revelli et al. was retro- and improve pregnancy outcomes; ICSI on the in-vitro spective, and three different types of medications were outcomes, and LT4 by preserving a normal thyroid func- given (LT4, acetyl-salicylic acid, and prednisolone) in a tion during pregnancy. Therefore, it make sense that the non-randomised way, and only a small number of patients negative results in the observational studies on the im- were included . Based on those two studies, the Ameri- pact of TAI in infertile women with TSH levels within can Thyroid Association (ATA) guidelines on the manage- pregnancy-specific reference range (usually ~ 4.0–4.5 ment of thyroid disorders during pregnancy found the mIU/L) and mainly treated with ICSI are in some way evidence insufficient to determine whether LT4 therapy predictive for negative study results in interventional tri- improves the success of pregnancy following ART in eu- als, and more in particular in that by Wang et al. . thyroid women with TAI, however, it is mentioned that In their discussion, the authors also mention that in a 25–50 μg LT4 may be considered given its potential bene- pooled analysis of 3 randomized clinical trials, LT4 treat- fits compared to its minimal risk . ment on pregnancy outcomes among women with TAI The results of the study by Wang et al. might weaken and a normal thyroid function significantly decreased the this ATA recommendation, but “let’s not throw the miscarriage rate (RR:0.45; 95% CI, 0.24–0.82) . How- (LT4) baby out with the bathwater”. Before concluding ever, in two of the three studies in that meta-analysis (> that LT4 is not effective to reduce miscarriage rates in 60% of all women included), serum TSH levels were > 4.0 euthyroid women with TAI, we believe the study results to 4.5 mIU/L and thus compatible with SCH and not a should be put in perspective with the current evidence normal thyroid function. In study by Wang et al., normal and thoroughly analysed. thyroid function was defined as a serum TSH < 4.7 mIU/ The incidence of miscarriage in clinically pregnancies L. Indeed, in the 2017 ATA guidelines, LT4 treatment for (< 20 gestational weeks) is 8–20%, and in case of the women with TPO-abs and a serum TSH above presence of TAI, it is up to 30% (4). Taking this into pregnancy-specific reference range (or > 4.0 mU/L if un- consideration, ~ 10% miscarriage rate in this study re- available) is strongly recommended . duces its power. In most studies, the diagnosis of TAI is based on the A few years ago in a meta-analysis on the association be- presence of TPO-abs only . However, in a prospective tween TAI and pregnancy outcomes after ART, an in- studydetermining thepresenceofTAI in infertilewomen, creased risk for a first trimester miscarriage was observed only positivity for Tg-abs was more frequent compared with compared with that in women without TAI . The odds that of TPO-abs . In the same study, women with only ratio (OR) in that study was 3.15, while in a recent Tg-abs also had higher mean serum TSH levels compared meta-analysis on the same association, the OR was only with women with only TPO-abs, and in a recent study in 1.44 . Two important reasons can be put forward for that China, women with Tg-abs had higher miscarriage rates decreasing OR, and at the same time, they might explain compared with women with TPO-abs . Not testing for (partially) the negative results in the study by Wang et al. A Tg-abs may therefore lead to misclassification, modify study firstreasoncan be theincreased useof ICSIastypeof conclusions and impair the management of pregnant ART, since ICSI can bias the impeding effects of thyroid women. The importance of Tg-abs is now also noticed in antibodies in the follicular fluid on the fertilization of the the ATA guidelines on the management of thyroid disor- egg, and therefore, be the more accurate type of ART in ders during pregnancy . Concerning the currently used women with TAI . Indeed, in a recent meta-analysis, in- cut-off for TPO-ab positivity, a recent study highlights that fertile women with TAI and all treated with ICSI (but not it may be too high. The authors found a dose-dependent with LT4), had comparable miscarriage (and live birth) rates relationship between TPO-ab levels and TSH as well as the as women without TAI . In the study by Wang et al. risk of premature delivery, and therefore, the use of a theprevalenceof women treated withICSIwas ~45% in population-based, pregnancy-specific, functional cut-off for both study groups. Another important point is the changed TPO-abs may be useful in the future . definition of a normal thyroid function and subclinical hypothyroidism (SCH) over the years. In the studies per- Conclusions formed before 2010, a normal thyroid function during the Before recommending against LT4 treatment in infertile first trimester of pregnancy was defined as a serum TSH women with TAI and serum TSH levels within Poppe et al. Thyroid Research (2018) 11:7 Page 3 of 3 pregnancy-specific reference range, we believe that more 8. Negro R, Mangieri T, Coppola L, Presicce G, Casavola EC, Gismondi R, et al. Levothyroxine treatment in thyroid peroxidase antibody-positive women studies are needed investigating the impact of thyroid undergoing assisted reproduction technologies: a prospective study. Hum function/TAI and ICSI on the in-vitro data (oocyte qual- Reprod. 2005;20:1529–33. ity, fertilization rate, embryo quality), the optimal LT4 9. Revelli A, Casano S, Piane LD, Grassi G, Gennarelli G, Guidetti D, et al. A retrospective study on IVF outcome in euthyroid patients with anti-thyroid dosage, and finally, optimising the diagnosis of TAI e.g. antibodies: effects of levothyroxine, acetyl-salicylic acid and prednisolone by taking Tg-abs into account as an equal marker as posi- adjuvant treatments. Reprod Biol Endocrinol. 2009;7:137. tivity for TPO-abs. In the meantime, physicians should 10. 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 judge case by case whether LT4 should be given, taking management of thyroid disease during pregnancy and the postpartum. into account other parameters such as baseline serum Thyroid. 2017;27:315–89. TSH levels, the obstetric history of the women, and the 11. Monteleone P, Parrini D, Faviana P, Carletti E, Casarosa E, Uccelli A, et al. Female infertility related to thyroid autoimmunity: the ovarian follicle cause of the infertility in the couple, with a particular at- hypothesis. Am J Reprod Immunol. 2011;66:108–14. tention in case of female and idiopathic infertility. 12. Poppe K, Autin C, Veltri F, Kleynen P, Grabczan L, Rozenberg S, et al. Thyroid autoimmunity and intracytoplasmic sperm injection outcome: a systematic Abbreviations review and meta-analysis. J Clin Endocrinol Metab. 2018;103:7155-66. ART: Assisted reproductive technology; ATA: American Thyroid Association; 13. De Groot L, Abalovich M, Alexander EK, Amino N, Barbour L, Cobin RH, et al. ICSI: Intra-cytoplasmic sperm injection; IVF: In-vitro fertilization; LT4: Levothyroxine; Management of thyroid dysfunction during pregnancy and postpartum: an SCH: Subclinical hypothyroidism; TAI: Thyroid autoimmunity; Tg-abs: Thyroglobulin Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012; antibodies; TPO-abs: Thyroid peroxidase antibodies 97:2543–65. 14. Lukaszuk K, Kunicki M, Kulwikowska P, Liss J, Pastuszek E, Jaszczołt M, et al. Authors’ contributions The impact of the presence of antithyroid antibodies on pregnancy KP wrote the commentary, FV and CA gave additional comments and/or outcome following intracytoplasmatic sperm injection-ICSI and embryo proposed changes. All authors read and approved the final manuscript. transfer in women with normal thyreotropine levels. J Endocrinol Investig. 2015;38:1335–43. Ethics approval and consent to participate 15. Mintziori G, Goulis DG, Gialamas E, Dosopoulos K, Zouzoulas D, Gitas G, Venetis Not applicable. CA, et al. Association of TSH concentrations and thyroid autoimmunity with IVF outcome in women with TSH concentrations within normal adult range. Competing interests Gynecol Obstet Investig. 2014;77:84–8. Kris Poppe reports speaker fees the IBSA Institut Biochimique SA (satellite 16. Unuane D, Velkeniers B, Deridder S, Bravenboer B, Tournaye H, De Brucker meeting of the European Thyroid Association) in 2016 and the Berlin-Chemie M. Impact of thyroid autoimmunity on cumulative delivery rates in in vitro AG company (ETA educational thyroid meeting) in 2017. The other authors fertilization/intracytoplasmic sperm injection patients. Fertil Steril. 2016;106: (CA, FV) declare no support from any organization. 144–50. 17. Velkeniers B, Van Meerhaeghe A, Poppe K, Unuane D, Tournaye H, Haentjens P. Levothyroxine treatment and pregnancy outcome in women with subclinical Publisher’sNote hypothyroidism undergoing assisted reproduction technologies. Hum Reprod Springer Nature remains neutral with regard to jurisdictional claims in Update. 2013;19:251–8. published maps and institutional affiliations. 18. Unuane D, Velkeniers B, Anckaert E, Schiettecatte J, Tournaye H, Haentjens P, Poppe K. Thyroglobulin autoantibodies: is there any added value in the Author details detection of thyroid autoimmunity in women consulting for fertility treatment? Endocrine Unit Centre Hospitalier Universitaire Saint Pierre, Rue Haute 322, Thyroid. 2013;23:1022–8. 1000 Brussels, Belgium. Departement of Gynecology, Obstetrics, and 19. Liu H, Shan Z, Li C, Mao J, Xie X, Wang W, et al. Maternal subclinical Reproductive Medicine Unit Centre Hospitalier Universitaire Saint Pierre, Rue hypothyroidism, thyroid autoimmunity, and the risk of miscarriage: a Haute 322, 1000 Brussels, Belgium. 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Published: May 30, 2018