Levothyroxine in Anti-Euthyroid Thyroid Peroxidase Antibody Positive Women with Recurrent Pregnancy Loss (T4LIFE Trial): A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial


Women positive for anti-thyroidase peroxidase (TPO-Ab) antibodies have a higher risk of recurrent miscarriage. Evidence on whether levothyroxine treatment improves pregnancy outcome in TPO-Ab positive women with recurrent pregnancy losses is sparse. The purpose of this study was to determine whether levothyroxine increases live birth rates in women who were TPO-Ab positive with recurrent pregnancy loss and normal thyroid function.


The T4LIFE trial was an international, phase 3, double-blind, placebo-controlled study conducted in 13 secondary and tertiary hospitals in the Netherlands, one tertiary hospital in Belgium and one tertiary hospital in Denmark. Women (18 to 42 years old) who were positive for anti-TPO antibodies, who had suffered at least two miscarriages, and whose thyroid-stimulating hormone (TSH) concentration was within the institutional reference range were eligible for the ‘inclusion. Women were excluded if they had antiphospholipid syndrome (lupus anticoagulant, anticardiolipin IgG or IgM antibody, or β2-glycoprotein-I IgG or IgM antibody), other autoimmune diseases, thyroid disease, prior enrollment in this trial or contraindications to the use of levothyroxine. Prior to 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 to 1.0 μg/kg body weight. Levothyroxine or placebo were continued until the end of pregnancy. The primary outcome was live birth, defined as a live birth beyond 24 weeks gestation measured in the intent-to-treat population. The trial was registered with the Netherlands Trials Register, NTR3364 and with EudraCT, 2011-001820-39.


Between January 1, 2013 and September 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 terminated prematurely when 187 (78%) of the predefined 240 patients had been included due to slow recruitment. 47 (50%) women in the levothyroxine group and 45 (48%) women in the placebo group had live births (relative risk 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 which were directly related to the study procedure.


Compared to placebo, levothyroxine treatment did not result in an increased live birth rate in euthyroid women with recurrent, anti-TPO antibody positive pregnancy losses. Based on our results, we do not advise the routine use of levothyroxine in women who are TPO-Ab positive with recurrent pregnancy loss and normal thyroid function.


Netherlands Organization for Health Research and Development, NutsOhra Fund, Netherlands Organization of Patients with Thyroid Disorders, Jan Dekkerstichting and Dr Ludgardine Bouwmanstichting, and a personal donation through the Netherlands Organization of Patients with Thyroid Disorders.

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