Levothyroxine treatment in euthyroid women positive for thyroid peroxidase antibodies and recurrent pregnancy loss

Miscarriage matters. For couples who have a miscarriage, it is a devastating experience with major physical and psychological consequences that are often under—estimated or even trivialised. 1 Quenby S Gallos ID Dhillon-Smith RK et al. Miscarriage matters: the epidemiological, physical, psychological, and economic costs of early pregnancy loss. Lancet. 2021; 397: 1658-1667 Summary Full Text Full Text PDF PubMed Scopus (112) Google Scholar Combined with the major health-economic effect on a population level, this makes research into miscarriage prevention and care a high priority. 1 Quenby S Gallos ID Dhillon-Smith RK et al. Miscarriage matters: the epidemiological, physical, psychological, and economic costs of early pregnancy loss. Lancet. 2021; 397: 1658-1667 Summary Full Text Full Text PDF PubMed Scopus (112) Google Scholar , 2 Coomarasamy A Dhillon-Smith RK Papadopoulou A et al. Recurrent miscarriage: evidence to accelerate action. Lancet. 2021; 397: 1675-1682 Summary Full Text Full Text PDF PubMed Scopus (22) Google Scholar Both the individual and population-based consequences of miscarriage are magnified for the approximate 2% of all women trying to conceive who have recurrent pregnancy losses. There are no proven effective preventative interventions for women with recurrent pregnancy losses; 2 Coomarasamy A Dhillon-Smith RK Papadopoulou A et al. Recurrent miscarriage: evidence to accelerate action. Lancet. 2021; 397: 1675-1682 Summary Full Text Full Text PDF PubMed Scopus (22) Google Scholar this can often lead to a no other option scenario in which treatments are started despite an absence of or scarce evidence for their efficacy. Of the known risk factors for miscarriage is seropositivity for thyroperoxidase antibodies (TPO-Abs), which has been associated with a 1·85–4-times higher risk of recurrent miscarriage, even in women who are euthyroid. 3 Thangaratinam S Tan A Knox E Kilby MD Franklyn J Coomarasamy A Association between thyroid autoantibodies and miscarriage and preterm birth: meta-analysis of evidence. BMJ. 2011; 342d2616 Crossref Scopus (342) Google Scholar TPO-Abs are clinically non-functioning IgG antibodies that reflect thyroid autoimmunity used for diagnosing autoimmune hypothyroidism. It has been hypothesised that the underlying mechanism for the higher risk of miscarriage could be either a relative thyroid hormone shortage, caused by a decreased thyroid functional capacity, or a higher general susceptibility to autoimmunity. In two high-quality randomised trials from China and the UK, levothyroxine treatment in euthyroid women who were TPO-Ab positive with subfertility or recurrent pregnancy losses did not lower the risk of miscarriage when compared with placebo or no treatment. 4 van Dijk MM Vissenberg R Fliers E et al. Levothyroxine in euthyroid thyroid peroxidase antibody positive women with recurrent pregnancy loss (T4LIFE trial): a multicentre, randomised, double-blind, placebo-controlled, phase3 trial. Lancet Diabetes Endocrinol. 2022; (published online March 14.)https://doi.org/10.1016/S2213-8587(22)00045-6 Summary Full Text Full Text PDF PubMed Scopus (4) Google Scholar , 5 Dhillon-Smith RK Middleton LJ Sunner KK et al. Levothyroxine in women with thyroid peroxidase antibodies before conception. N Engl J Med. 2019; Crossref Scopus (126) Google Scholar Because women with recurrent pregnancy losses were not the primary focus of the aforementioned randomised trials, levothyroxine treatment is still considered in this population, especially if the thyroid stimulating hormone (TSH) concentration is above 2·5 mU/L. Levothyroxine in euthyroid thyroid peroxidase antibody positive women with recurrent pregnancy loss (T4LIFE trial): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trialCompared with placebo, levothyroxine treatment did not result in higher live birth rates in euthyroid women with recurrent pregnancy loss who were positive for TPO-Ab. On the basis of our findings, we do not advise routine use of levothyroxine in women who are TPO-Ab positive with recurrent pregnancy loss and normal thyroid function. Full-Text PDF