From Pages to Practice

By Amanda Fernandes, MD

Published January 5, 2022


Mrs. Nettle is a 35-year-old woman who has been trying to conceive for the past 6 months. Otherwise healthy, she was recently evaluated for infertility. Initial laboratory evaluation noted normal thyroid stimulating hormone but positive thyroid peroxidase antibodies. She had read that thyroid peroxidase antibodies might be related to infertility and miscarriage. She asks if she should be taking thyroid hormone supplementation. 

In a double-blind, placebo-controlled trial published in the NEJM, Dhillon-Smith and colleagues reported that once-daily levothyroxine taken throughout pregnancy did not result in higher rates of live births, compared with placebo, in euthyroid women with known positive thyroid peroxidase antibodies and a history of miscarriage or infertility. For Mrs. Nettle, results of this study suggest that thyroid hormone supplementation is unlikely to affect infertility and miscarriage.

The following NEJM Journal Watch summary further explains the study.


Live Birth Rates in Euthyroid Women with Thyroid Peroxidase Antibodies

Randomized trial showed no benefit of exogenous levothyroxine in women with histories of infertility or miscarriage.

Euthyroid women with thyroid peroxidase antibodies are at excess risk for miscarriage and preterm birth, but whether exogenous levothyroxine is beneficial to such women remains unknown. Investigators in the U.K. conducted a multicenter trial in which 952 euthyroid women (age range, 16–40) with a history of miscarriage or infertility and seeking to conceive were randomized to 50-µg oral levothyroxine or placebo daily from before conception through the end of pregnancy. Euthyroid status was defined as serum thyrotropin 0.44–3.63 mIU/L and free thyroxine 10.0–21.0 pmol/L (0.78–1.63 ng/dL). Group assignments were balanced by age (<35 or ≥35), number of previous miscarriages, infertility treatment, and baseline thyrotropin concentration (≤2.5 or >2.5 mIU/L). Adherence to levothyroxine was confirmed by measuring serum thyrotropin and free thyroxine.

Live-birth rates after ≥34 weeks’ gestation were 37.4% (levothyroxine) and 37.9% (placebo; relative risk, 0.97). Subgroup analysis by factors such as maternal age, number of previous miscarriages, and baseline thyrotropin also showed no significant between-group differences in live birth, pregnancy loss, preterm birth, or neonatal outcomes. Serious adverse events did not differ between groups.

Comment: Although this trial is limited because the entire intervention group received the same dose of levothyroxine, the results should put to rest the possibility of using exogenous levothyroxine to treat euthyroid women positive for thyroid peroxidase antibodies. Perhaps the findings are to be expected, as the principal association with infertility and miscarriage involves thyroid peroxidase antibodies, not circulating thyroxine — and these antibody levels were not directly lowered by treatment. The study also suggests that thyroid peroxidase antibody testing in euthyroid women with histories of miscarriage or infertility may be unnecessary, given the failure of exogenous levothyroxine to lower risks for miscarriage or infertility.

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Amanda Fernandes is a 2018-2019 NEJM editorial fellow.