Levothyroxine in euthyroid thyroid peroxidase antibody positive women with recurrent pregnancy loss (T4LIFE trial): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Dijk, Myrthe M. van; Vissenberg, Rosa; Fliers, Eric; Post, Joris A. M. van der; Hoorn, Marie-Louise van der; Weerd, Sabina de; Kuchenbecker, Walter K. H.; Hoek, Annemieke; Sikkema, J.; Verhoeve, Harold R.; Broeze, Kimiko A.; Koning, Corry H de; Verpoest, Willem; Christiansen, Ole Bjarne; Koks, Carolien A.M.; Bruin, Jan Peter de; Papatsonis, Dimitri; Torrance, Helen L.; Wely, Madelon van; Bisschop, Peter H.; Goddijn, Mariëtte

doi:10.1016/s2213-8587(22)00045-6

Cited by 55 publications

(36 citation statements)

References 23 publications

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“…It remains difficult to determine whether levothyroxine treatment is of benefit in TPOAb positive women during pregnancy. We have now learned from three well-performed randomized trial that there is no benefit of preconception levothyroxine treatment for euthyroid TPOAb positive women [25][26][27]. However, the randomized trial data for gestational levothyroxine treatment of euthyroid TPOAb positivity are poor since there are no randomized trials focusing primarily on euthyroid TPOAb positivity but only subanalyses can be identified.…”

Section: Levothyroxine Treatmentmentioning

confidence: 99%

Euthyroid Thyroperoxidase Antibody Positivity during Pregnancy, to Treat or Not to Treat?

Korevaar¹

2022

Endocrinol Metab

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Thyroperoxidase antibody (TPOAb) positivity is a well-known risk factor for thyroid dysfunction during pregnancy and is associated with a suboptimal response to thyroidal stimulation by human chorionic gonadotropin. About 75% of TPOAb positive women are euthyroid and there seems to be a higher risk of predominantly miscarriage and preterm birth in this subgroup. Nonetheless, clinical decision making with regards to gestational levothyroxine treatment remains difficult due to a lack of large randomized trials. Future studies assessing dose-dependent associations and additional biomarkers that can distinguish low-risk from high-risk individuals will be key in disentangling the crude clinical data.

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Section: Levothyroxine Treatmentmentioning

confidence: 99%

Euthyroid Thyroperoxidase Antibody Positivity during Pregnancy, to Treat or Not to Treat?

Korevaar¹

2022

Endocrinol Metab

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“…In conclusion, an effective treatment to prevent them is still unavailable, although evidence has suggested that euthyroid females with AIT have a high risk of experiencing adverse obstetric outcomes. This was further confirmed by the recent T4LIFE trial, which showed that LT4 administration did not result in higher live birth rates in patients with AIT with euthyroidism with recurrent pregnancy loss [ 88 ], thus leading to research on other treatment strategies.…”

Section: Autoimmune Thyroiditis In Pregnancymentioning

confidence: 74%

Selenium Supplementation in Pregnant Women with Autoimmune Thyroiditis: A Practical Approach

et al. 2022

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Selenium (Se) is an essential trace element with antioxidant and anti-inflammatory properties and a pivotal role in thyroid metabolism. Ensuring a sufficient Se supply is possible via a balanced, wholesome diet; however, Se content in foods may be different throughout geographical areas. Se supplementation is expected to improve inflammatory status in patients with autoimmune thyroiditis, especially in those with high activity, and has been demonstrated as effective in reducing the thyroid peroxidase antibodies titer. Se status seems to affect thyroid function in pregnancy, which prompts the potential role of Se supplementation in such patients. Few clinical trials have investigated the effectiveness of Se supplementation in pregnant women with thyroiditis, and their results suggest the safety and effectiveness of this element in reducing autoantibody levels and preventing postpartum thyroiditis development, although limited. Hence, more robust evidence is needed to confirm these data. The current study aims to summarize published data on the relationship between Se and thyroid status in pregnant women with thyroiditis and the potential use of Se. Moreover, an algorithm for Se supplementation is proposed for pregnant women with thyroiditis to help endocrinologists in daily clinical practice to consider Se status.

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“…The ATA also proposed considering levothyroxine for women with thyroid autoimmunity and TSH above 2.5 mIU/L and for euthyroid infertile women with a history of pregnancy loss. After the publication of the ATA guidelines, several important randomized clinical trials (RCTs) were released, which makes it necessary to reconsider this perspective ( Table 1 ) ( 84 – 90 ). Moreover, four meta-analyses including only RCTs could not find any evidence that levothyroxine supplementation in euthyroid women with AITD resulted in an improvement in maternal pregnancy outcomes ( 94 – 97 ).…”

Section: Treatment Optionsmentioning

confidence: 99%

“…The results of the meta-analyses have also shown that initiating levothyroxine during the preconception period or in the first trimester did not affect the miscarriage risk. Finally, the highly anticipated T4-LIFE trial addressing the impact of levothyroxine treatment in TPOAb-positive euthyroid women with recurrent miscarriage was published, and the levothyroxine intervention failed again to decrease the risk of pregnancy loss ( 90 ). Although these observations require further analysis, the only beneficial effect of levothyroxine treatment in TAI women documented so far is prevention of hypothyroidism.…”

Section: Treatment Optionsmentioning

confidence: 99%

Thyroid autoimmunity and its negative impact on female fertility and maternal pregnancy outcomes

et al. 2023

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Thyroid autoimmunity (TAI) is commonly defined as the presence of thyroperoxidase antibodies (TPOAbs) and/or thyroglobulin antibodies (TgAbs), which predisposes an individual to hypothyroidism. TAI affects nearly 10% of women of reproductive age and evokes great interest from clinicians because of its potentially negative impact on female fertility and pregnancy course. In this mini-review, we review the current literature concerning the influence of TPOAb or TPOAb/TgAb positivity without thyroid dysfunction on reproduction. TAI may negatively affect female fertility; several studies have found an increased prevalence of TAI in infertile women, especially in those with unexplained infertility and polycystic ovary syndrome. According to some observations, TAI might also be connected with premature ovarian insufficiency and endometriosis. The relationship between TAI and an increased risk of pregnancy loss is well documented. The pathophysiological background of these observations remains unclear, and researchers hypothesize on the direct infiltration of reproductive organs by thyroid antibodies, co-existence of TAI with other autoimmune diseases (either organ specific or systemic), immunological dysfunction leading to inhibition of immune tolerance, and relative thyroid hormone deficiency. Interestingly, in the current literature, better outcomes of assisted reproductive technology in women with TAI have been reported compared with those reported in earlier publications. One plausible explanation is the more widespread use of the intracytoplasmic sperm injection method. The results of randomized clinical trials have shown that levothyroxine supplementation is ineffective in preventing adverse pregnancy outcomes in women with TAI, and future research should probably be directed toward immunotherapy.

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Levothyroxine in euthyroid thyroid peroxidase antibody positive women with recurrent pregnancy loss (T4LIFE trial): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Cited by 55 publications

References 23 publications

Euthyroid Thyroperoxidase Antibody Positivity during Pregnancy, to Treat or Not to Treat?

Euthyroid Thyroperoxidase Antibody Positivity during Pregnancy, to Treat or Not to Treat?

Selenium Supplementation in Pregnant Women with Autoimmune Thyroiditis: A Practical Approach

Thyroid autoimmunity and its negative impact on female fertility and maternal pregnancy outcomes

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