The presence of thyroid peroxidase antibodies (TPOAb) often precedes thyroid disease. In addition, even in euthyroid women, TPOAbs are strongly associated with miscarriage and preterm birth. Several randomized trials have examined the utility of providing thyroid hormone supplementation (with levothyroxine; LT4) to euthyroid women with TPOAbs to prevent adverse pregnancy outcomes. These studies gave conflicting results. Two studies suggested LT4 treatment decreased the rate of miscarriage. One examined 115 unselected women and the other involved 72 women undergoing assisted reproductive techniques. The third study examined 600 women undergoing IVF, and concluded that LT4 did not decrease miscarriage or preterm birth.  

The American Thyroid Association stated in their 2017 guidelines that there was insufficient evidence to conclusively determine whether LT4 therapy decreases risk of miscarriage in TPOAb positive, euthyroid patients. However they did state that LT4 administration may be considered in TPOAb positive euthyroid pregnant women with a history of pregnancy loss.

Recently, researchers from the UK published the largest multi-center, randomized, placebo-controlled trial to date examining LT4 therapy in TPOAb positive, euthyroid patients. The study screened 19,556 women for eligibility. Women were eligible if they were 16-40 years of age, had a history of miscarriage or infertility and were trying to conceive.  They were excluded if they were receiving treatment for a thyroid disorder, had cardiac disease or were receiving lithium or amiodarone treatment.  Euthyroidism was defined as TSH 0.44-3.63 mIU/L. TSH was measured on Abbott, Roche and Siemens platforms. TPOAbs were measured on multiple unspecified devices.

1420 women were found to be eligible for enrollment and 952 of those consented to participate. The women were then randomly assigned to once daily 50 mg LT4 (n=476) or placebo therapy (n=476). Therapy began immediately (i.e. before pregnancy) and continued throughout pregnancy. 6 women in each group were lost to follow-up or withdrew from the study. As expected, TSH concentrations were lower and fT4 concentrations higher in the LT4 group than placebo.

I’ve listed the results of their primary and some of their secondary outcomes below.

OutcomeLT4PlaceboRelative Risk (95% CI)
Primary Outcome
Live Birth at ≥34 wk176/470 (37.4%)178/470 (37.9%)0.97 (0.83-1.14)
Secondary Outcome
Pregnancy after enrollment266/470 (56.6%)274/470 (58.3%)0.97 (0.88-1.07)
Miscarriage at <24 wks75/266 (28.2%)81/274 (29.6%)0.95 (0.73-1.23)
Live birth <34 wks10/266 (3.8%)10/274 (3.6%)1.02 (0.43-2.42)

The group found no significant differences in live birth rate after 34 weeks, or in any of the maternal or neonatal complications. The authors did discuss the use of multiple TPO assays with different detection limits as a limitation of their study, although, as they state, this is an accepted part of normal practice.

This study does not support the use of LT4 in TPOAb positive, euthyroid patients trying to achieve pregnancy.

Originally published by The Pregnancy Lab

About The Author

Professor of Pathology & Immunology, and Obstetrics & Gynecology, Washington University School of Medicine

Dr. Gronowski is a Professor of Pathology & Immunology, and Obstetrics & Gynecology at Washington University School of Medicine (St. Louis Missouri). She is Associate Medical Director of the Clinical Chemistry and Serology & Immunology laboratories at Barnes-Jewish Hospital. Dr. Gronowski received her Ph.D. in Endocrinology- Reproductive Physiology from University of Wisconsin, and is a diplomate of the American Board of Clinical Chemistry. Dr. Gronowski is past president of the American Board of Clinical Chemistry and the American Association for Clinical Chemistry. Her research focuses primarily on the laboratory diagnostics of endocrinology and reproductive physiology with a particular emphasis on maternal fetal medicine. She edited the book entitled “Handbook of Clinical Laboratory Testing During Pregnancy”.