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.

中文翻译：

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左甲状腺素在甲状腺功能正常、甲状腺过氧化物酶抗体阳性的复发性流产妇女中的应用（T4LIFE 试验）：一项多中心、随机、双盲、安慰剂对照的 3 期试验

背景

甲状腺过氧化物酶抗体 (TPO-Ab) 阳性的女性复发性流产的风险更高。关于左甲状腺素治疗是否能改善 TPO-Ab 阳性且反复流产的女性的妊娠结局的证据很少。本研究的目的是确定左甲状腺素是否会增加 TPO-Ab 阳性、反复流产且甲状腺功能正常的女性的活产率。

方法

T4LIFE 试验是一项国际性、双盲、安慰剂对照的 3 期研究，在荷兰的 13 家二级和三级医院、比利时的一家三级医院和丹麦的一家三级医院进行。TPO-Ab 阳性、两次或多次流产且促甲状腺激素 (TSH) 浓度在机构参考范围内的女性 (18-42 岁) 有资格入选。如果女性患有抗磷脂综合征（狼疮抗凝剂、抗心磷脂 IgG 或 IgM 抗体，或 β2-糖蛋白-I IgG 或 IgM 抗体）、其他自身免疫性疾病、甲状腺疾病、先前参与本试验或有左旋甲状腺素使用禁忌症，则被排除在外。受孕前，女性被随机分配（1:1）每天口服一次左旋甲状腺素或安慰剂。左甲状腺素的日剂量基于孕前 TSH 浓度，范围为 0·5–1·0 μg/kg 体重。左甲状腺素或安慰剂持续到妊娠结束。主要结局是活产，定义为在意向治疗人群中测量的妊娠超过 24 周的活儿出生。该试验已在荷兰试验注册中心 NTR3364 和 EudraCT 注册，2011-001820-39。

结果

在 2013 年 1 月 1 日至 2019 年 9 月 19 日期间，187 名女性被纳入研究：94 名（50%）被分配到左甲状腺素组，93 名（50%）被分配到安慰剂组。由于招募缓慢，当 240 名预定义患者中的 187 名（78%）被纳入时，该试验提前停止。左甲状腺素组 47 名 (50%) 女性和安慰剂组 45 名 (48%) 女性活产（风险比 1·03 [95% CI 0·77 至 1·38]；绝对风险差异 1·6% [95% CI –12·7 至 15·9]）。左甲状腺素组的七名 (7%) 女性和安慰剂组的七名 (8%) 女性报告了不良事件，其中没有一个与研究程序直接相关。

解释

与安慰剂相比，左旋甲状腺素治疗并未导致甲状腺功能正常且 TPO-Ab 阳性的复发性流产妇女的活产率更高。根据我们的研究结果，我们不建议在 TPO-Ab 阳性、反复流产且甲状腺功能正常的女性中常规使用左旋甲状腺素。

资金

荷兰健康研究与发展组织、Fonds NutsOhra、荷兰甲状腺疾病患者组织、Jan Dekkerstichting 和 Ludgardine Bouwmanstichting 博士，以及来自荷兰甲状腺疾病患者组织的个人捐赠。