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Effect of Levothyroxine on Miscarriage Among Women With Normal Thyroid Function and Thyroid Autoimmunity Undergoing In Vitro Fertilization and Embryo TransferA Randomized Clinical Trial

Educational Objective
To understand the effect of treatment with levothyroxine on pregnancy outcomes in women undergoing in vitro fertilization and embryo transfer with a functioning thyroid who tested positive for autoimmunity.
1 Credit CME
Key Points

Question  Does levothyroxine treatment improve outcomes following in vitro fertilization and embryo transfer in women who have tested positive for thyroid autoantibodies but otherwise have normal thyroid function?

Findings  In this randomized clinical trial involving 600 women undergoing in vitro fertilization and embryo transfer who tested positive for antithyroperoxidase antibodies but who had a normal thyroid function, the miscarriage rate before 28 weeks’ gestation was 10.3% among women who received and 10.6% among those who did not receive levothyroxine, a nonsignificant difference.

Meaning  Levothyroxine treatment did not appear to improve pregnancy outcomes among women with thyroid autoantibodies undergoing in vitro fertilization and embryo transfer.

Abstract

Importance  Presence of thyroid autoantibodies in women with normal thyroid function is associated with increased risk of miscarriage. Whether levothyroxine treatment improves pregnancy outcomes among women undergoing in vitro fertilization and embryo transfer (IVF-ET) is unknown.

Objective  To determine the effect of levothyroxine on miscarriage among women undergoing IVF-ET who had normal thyroid function and tested positive for thyroid autoantibodies.

Design, Setting, and Participants  An open-label, randomized clinical trial involving 600 women who tested positive for the antithyroperoxidase antibody and were being treated for infertility at Peking University Third Hospital from September 2012 to March 2017.

Interventions  The intervention group (n = 300) received either a 25-μg/d or 50-μg/d dose of levothyroxine at study initiation that was titrated according to the level of thyroid-stimulating hormone during pregnancy. The women in the control group (n = 300) did not receive levothyroxine. All participants received the same IVF-ET and follow-up protocols.

Main Outcomes and Measures  The primary outcome was the miscarriage rate (pregnancy loss before 28 weeks of gestation, which was calculated among women who became pregnant). The secondary outcomes were clinical intrauterine pregnancy rate (fetal cardiac activity seen at sonography observation on the 30th day after the embryo transfer), and live-birth rate (at least 1 live birth after 28 weeks of gestation).

Results  Among the 600 women (mean [SD] age, 31.6 [3.8] years) randomized in this trial, 567 women (94.5%) underwent IVF-ET and 565 (94.2%) completed the study. Miscarriage rates were 10.3% (11 of 107) in the intervention group and 10.6% (12 of 113) in the control group, with the absolute rate difference (RD) of −0.34% (95% CI, −8.65% to 8.12%) over the 4.5-year study period. Clinical intrauterine pregnancy rates were 35.7% (107 of 300) in the intervention group and 37.7% (113 of 300) in the control group, with an absolute RD of −2.00% (95% CI, −9.65% to 5.69%). Live-birth rates were 31.7% (95 of 300) in the intervention group and 32.3% (97 of 300) in the control group, with an absolute RD of −0.67% (95% CI, −8.09% to 6.77%).

Conclusions and Relevance  Among women in China who had intact thyroid function and tested positive for antithyroperoxidase antibodies and were undergoing IVF-ET, treatment with levothyroxine, compared with no levothyroxine treatment, did not reduce miscarriage rates or increase live-birth rates.

Trial Registration  Chinese Clinical Trial Registry: ChiCTR-TRC-13004097

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Article Information

Corresponding Authors: Jie Qiao, MD, PhD, Center of Reproductive Medicine, and Tianpei Hong, MD, PhD, Department of Endocrinology and Metabolism, Peking University Third Hospital, 49 N Garden Rd, Haidian District, Beijing 100191, China (jie.qiao@263.net and tpho66@bjmu.edu.cn).

Accepted for Publication: November 1, 2017.

Author Contributions: Drs H. Wang and Chi had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs H. Wang, Gao, Chi, and Zeng contributed equally as first authors to this work. Drs Qiao and Hong jointly directed this work and contributed equally as corresponding authors.

Concept and design: H. Wang, Gao, Chi, Zeng, Xiao, Y. Wang, Li, Zhou, Hong, Qiao.

Acquisition, analysis, or interpretation of data: H. Wang, Gao, Chi, Zeng, Li, P. Liu, C. Wang, Tian, Yang, Y. Liu, Wei, Mol, Hong, Qiao.

Drafting of the manuscript: H. Wang, Gao, Chi, Zeng, Xiao, Li, Zhou.

Critical revision of the manuscript for important intellectual content: H. Wang, Gao, Chi, Y. Wang, Li, P. Liu, C. Wang, Tian, Yang, Y. Liu, Wei, Mol, Hong, Qiao.

Statistical analysis: H. Wang, Gao, Zeng.

Obtained funding: Hong, Qiao.

Administrative, technical, or material support: H. Wang, Gao, Chi, Xiao, Li, C. Wang, Tian, Zhou, Yang, Y. Liu, Wei, Mol, Hong, Qiao.

Supervision: Gao, Zeng, Hong, Qiao.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Mol reported that he received grant support from the National Health and Medical Research Council (GNT1082548) and has served as a consultant for ObsEva, Merck, and Guerbet. No other financial conflicts were reported.

Funding/Support: This study was supported by grants 2015BAI13B06 from the National Key Technology R&D Program and 2012CB517502 and from the Chinese National 973 Program, both from the Ministry of Science and Technology of China.

Role of the Funder/Sponsor: The Ministry of Science and Technology of China had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank Jinlan Dong, BS; Lin Zhang, MD; Li Chen, BS; Xin Wang, BS; Qun Wang, BS; Zheng Ma, BS, who collected and tested all samples throughout the trial. They are all from Department of Endocrinology and Metabolism, Peking University Third Hospital. They received no compensation for their contributions. We thank all the women whose participation made this study possible. None of those participants were compensated for their contribution.

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