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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

https://doi.org/10.1016/S2213-8587(22)00045-6Get rights and content

Summary

Background

Women positive for thyroid peroxidase antibodies (TPO-Ab) have a higher risk of recurrent pregnancy loss. Evidence on whether levothyroxine treatment improves pregnancy outcomes in women who are TPO-Ab positive women with recurrent pregnancy loss is scarce. The aim of this study was to determine if levothyroxine increases live birth rates in women who were TPO-Ab positive with recurrent pregnancy loss and normal thyroid function.

Methods

The T4LIFE trial was an international, double-blind, placebo-controlled, phase 3 study done in 13 secondary and tertiary hospitals in the Netherlands, one tertiary hospital in Belgium, and one tertiary hospital in Denmark. Women (18–42 years) who were TPO-Ab positive, had two or more pregnancy losses, and had a thyroid stimulating hormone (TSH) concentration within the institutional reference range were eligible for inclusion. Women were excluded if they had antiphospholipid syndrome (lupus anticoagulant, anticardiolipin IgG or IgM antibodies, or β2-glycoprotein-I IgG or IgM antibodies), other autoimmune diseases, thyroid disease, previous enrolment in this trial, or contraindications for levothyroxine use. Before conception, women were randomly assigned (1:1) to receive either levothyroxine or placebo orally once daily. The daily dose of levothyroxine was based on preconception TSH concentration and ranged from 0·5–1·0 μg/kg bodyweight. Levothyroxine or placebo was continued until the end of pregnancy. The primary outcome was live birth, defined as the birth of a living child beyond 24 weeks of gestation measured in the intention-to-treat population. The trial was registered within the Netherlands Trial Register, NTR3364 and with EudraCT, 2011-001820-39.

Results

Between Jan 1, 2013, and Sept 19, 2019, 187 women were included in the study: 94 (50%) were assigned to the levothyroxine group and 93 (50%) were assigned to the placebo group. The trial was prematurely stopped when 187 (78%) of the 240 predefined patients had been included because of slow recruitment. 47 (50%) women in the levothyroxine group and 45 (48%) women in the placebo group had live births (risk ratio 1·03 [95% CI 0·77 to 1·38]; absolute risk difference 1·6% [95% CI –12·7 to 15·9]). Seven (7%) women in the levothyroxine group and seven (8%) in the placebo group reported adverse events, none of them were directly related to the study procedure.

Interpretation

Compared 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.

Funding

Dutch Organization for Health Research and Development, Fonds NutsOhra, Dutch Patient Organization of Thyroid Disorders, the Jan Dekkerstichting and Dr Ludgardine Bouwmanstichting, and a personal donation through the Dutch Patient Organization of Thyroid Disorders.

Introduction

Recurrent pregnancy loss—defined as the loss of two or more pregnancies—is a significant health problem, affecting the physical and psychological wellbeing of prospective parents. It is a devastating experience for most couples and often leads to a long process of consulting multiple physicians and clinics in search for a cause and treatment.1 Approximately 2% of women trying to conceive have recurrent pregnancy loss.2

Women positive for thyroid peroxidase antibodies (TPO-Ab) have a higher risk of single pregnancy loss and recurrent pregnancy loss.3, 4 TPO-Ab positivity is also associated with other pregnancy complications, including unexplained subfertility, preterm birth, and postpartum thyroiditis.3, 4 A leading hypothesis for this association is that women positive for TPO-Ab have a chronic lymphocytic thyroiditis that has not yet led to hypothyroidism. Subclinical or overt hypothyroidism can become apparent in early pregnancy because of the increased need for thyroid hormone.5 Moreover, women positive for TPO-Ab have an impaired normal physiological thyroidal response to human chorionic gonadotropin in early pregnancy;6 therefore, levothyroxine supplementation has been proposed to reduce the risk of pregnancy complications.

Research in context

Evidence before this study

We searched PubMed for studies published between the inception of the database and Nov 1, 2021, using the search terms (“recurrent miscarriage” OR “recurrent pregnancy loss”) AND (“thyroid peroxidase antibodies” OR “thyroid autoimmunity”) to find randomised trials and meta-analyses of randomised trials, published in English, that evaluated the effectiveness of levothyroxine supplementation on live birth rates in women with thyroid peroxidase antibodies (TPO-Ab) and recurrent pregnancy loss. We did not find any randomised trials that included women with recurrent pregnancy loss, but we did find a meta-analysis of 2263 women who were TPO-Ab positive enrolled in six randomised trials. None of the included studies in this meta-analysis focused on women with recurrent pregnancy loss. No differences in pregnancy loss rates and live birth were found in women positive for TPO-Ab who received levothyroxine compared with control groups. The large randomised TABLET trial, included in the meta-analysis, did a subgroup analysis of women with recurrent pregnancy loss. No effect of levothyroxine was seen on live birth rates in women positive for TPO-Ab and recurrent pregnancy loss compared with placebo (RR 1·04 [95% CI 0·72–1·51). However, the TABLET trial did not exclude women with other risk factors for recurrent pregnancy loss besides TPO-Ab, which reduced the likelihood of a beneficial effect of levothyroxine for this subgroup. In the TABLET trial a fixed dose of levothyroxine was used, which did not reduce the number of abnormal thyroid function tests during pregnancy in comparison with placebo.

Added value of this study

Our international, double-blind randomised trial focussed on women with recurrent pregnancy loss who were positive for TPO-Ab. Levothyroxine was dosed depending on the participant's body weight and thyroid stimulating hormone concentration. There was no significant difference in live birth rate between the levothyroxine and placebo groups. There was also no evidence of a difference in any of the secondary outcomes, including pregnancy losses, ongoing pregnancy rates, and preterm birth.

Implications of all the available evidence

Routine use of levothyroxine in women with recurrent pregnancy loss, normal thyroid function, and positive for TPO-Ab is not recommended.

Starting levothyroxine preconceptionally would correct a possible thyroid hormone deficiency in the earliest phase of pregnancy. Previously published studies initiated levothyroxine during pregnancy.7, 8 The most recent developments in this area are two large randomised trials that investigated the effect of levothyroxine supplementation started before conception on live birth rates in euthyroid TPO-Ab positive women with a history of infertility or pregnancy loss9 or undergoing in-vitro fertilisation (IVF).10 Neither study found evidence that levothyroxine affected live birth rate.5, 6 A systematic review and meta-analysis including six trials found no difference in pregnancy loss rates (relative risk [RR] 0·93 [95% CI 0·76–1·14]) and live birth rates (RR 1·01 [0·89–1·16]) in women positive for TPO-Ab treated with levothyroxine compared with controls.11 None of these studies focused on women with recurrent pregnancy loss.

Supplementation of levothyroxine in women who are TPO-Ab positive with normal thyroid function and recurrent pregnancy loss remains controversial due to a scarcity of evidence specific for this population. The European Society of Human Reproduction and Embryology Guideline on Recurrent Pregnancy Loss states that there is not enough evidence to support levothyroxine treatment outside of clinical trials.12 The guidelines of the American Thyroid Association state that supplementation of levothyroxine in TPO-Ab positive women with recurrent pregnancy loss might be considered given its potential benefits in comparison with its minimal risk.13 Neither the dated guidelines of the American Society for Reproductive Medicine nor the Royal College of Obstetricians and Gynaecologist recommend treatment of women who were TPO-Ab positive with a history of recurrent pregnancy loss.14, 15

We are faced with conflicting recommendations from international guidelines due to a scarcity of high-quality evidence on the efficacy of levothyroxine treatment in euthyroid women who are TPO-Ab positive with recurrent pregnancy loss. We aimed to determine if levothyroxine increases live birth rates in women who were TPO-Ab positive with recurrent pregnancy loss and normal thyroid function.

Section snippets

Study design and participants

The T4LIFE trial was a multicentre, randomised, double-blind, placebo-controlled study done in 15 hospitals. 13 hospitals were in the Netherlands (four university hospitals and nine non-university hospitals)—all of which collaborated in the Dutch Consortium for Women's Health Research—one university hospital in Belgium, and one university hospital in Denmark.

Women with two or more pregnancy losses were diagnostically tested for recurrent pregnancy loss in the participating centres, including

Results

Between Jan 1, 2013, and Sept 19, 2019, 187 women consented to participate and were randomly assigned to the levothyroxine group (94 [50%] women) or the placebo group (93 [50%] women). The trial was prematurely stopped because of slow recruitment when 187 (78%) of the 240 predefined patients had been included.

Baseline characteristics were similar between the levothyroxine group and placebo group (table 1). Follow-up data were available for the primary outcome in 172 (92%) of the 187 women. Two

Discussion

Our international, double-blind, randomised trial showed no significant differences in live birth rate after levothyroxine treatment in women with recurrent pregnancy loss who were positive for TPO-Ab compared with placebo. There was also no evidence of a difference in any of the secondary outcomes, including pregnancy losses, ongoing pregnancy rates, and preterm birth.

Our study provides added value in the field of recurrent pregnancy loss research, in which large treatment trials to date are

Data sharing

Deidentified participant data, study protocol, and the statistical analysis plan will be made available with publication. The deidentified participant data can be requested by contacting the corresponding author after approval of a proposal and with a signed data access agreement.

Declaration of interests

MG received research and educational grants from Guerbet, Merck, and Ferring, not related to the presented work, paid to their institution. AH reports an unrestricted educational grant from Ferring, not related to the presented work, paid to their institution. All other authors declare no competing interests.

References (24)

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    Effect of levothyroxine on miscarriage among women with normal thyroid function and thyroid autoimmunity undergoing in vitro fertilization and embryo transfer: a randomized clinical trial

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      Citation Excerpt :

      In a randomized controlled trial published in 2017, women with intact thyroid function and positive TPO-Ab undergoing IVF and embryo transfer, treatment with levothyroxine did not decrease the miscarriage rates or increase the LBRs compared with no treatment (112). Similarly, in another randomized controlled trial, the use of levothyroxine in euthyroid women with thyroid peroxidase antibodies did not result in higher LBRs than placebo (113), whereas more recently, levothyroxine treatment in euthyroid women with positive TPO-Ab and recurrent pregnancy loss did not result in higher LBRs (112). Overall, although it is clear that thyroid function must be assessed in all women with infertility planning to become pregnant, recent studies seriously question whether treatment is essential only in the presence of TPO-Ab when no clinical hypothyroidism is demonstrated.

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    Authors contributed equally

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