Does The Use of Levothyroxine in Women with Thyroid Peroxidase Antibodies Affect The Risk of Miscarriage and Premature Birth?

Observed Patient Population

The double-blind, placebo-controlled study included 940 women with thyroid peroxidase antibodies and euthyroid (defined as a TSH concentration in the range of 0.44–3.36 mIU/l and fT4 in the range of 10.0–21.0 pmol/l). Data from subsequent follow-ups were available for the assessed women. The inclusion criteria were as follows: age 16–40 years, history of miscarriage or infertility, and planned conception in the next 12 months (naturally or through assisted reproduction). Conversely, women using thyroid medications, amiodarone, lithium, or those with cardiac disease were not included in the study.

Patients were further subdivided into subgroups according to age (< 35 and ≥ 35 years), number of previous miscarriages, infertility treatment (yes/no), TSH concentration (≤ 2.5 and > 2.5 mIU/l), race and ethnic group, antibody concentration (≥ 50th and < 50th percentile), and BMI (< 25 and ≥ 25 kg/m²).

Methodology and Study Process

A total of 19,556 women were screened and tested for thyroid peroxidase antibodies. The women included in the study were randomly divided into two groups of 470 participants each: patients in the first group took levothyroxine daily at a dose of 50 µg, while the second group was given a placebo. Medication was started before planned conception and continued until possible delivery. Thyroid function was tested every 3 months over the next 12 months, and in the case of pregnancy, at the 6th-8th week, 16th-18th week, and finally at the 28th week of pregnancy.

Pregnancy was confirmed by a urine test, followed by an ultrasound examination at the 6th-8th week of pregnancy. Miscarriage criteria included a subsequent negative ultrasound examination or negative urine pregnancy test.

Aside from the proportion of women who gave birth to live babies after the 34th week of pregnancy, the study also monitored secondary parameters: clinical pregnancy at the 7th week, ongoing pregnancy at the 12th week, miscarriage before the 24th week, intrauterine fetal death before the 24th week, ectopic pregnancy, pregnancy termination, live birth before the 28th, 34th, and 37th week, week of pregnancy at delivery, birth weight (in grams), Apgar score at 1 and 5 minutes, prenatal, intrapartum, and postpartum complications in the mother, and neonatal complications.

Study Results

A total of 266 out of 470 women taking levothyroxine became pregnant (56.6%), compared to 274 out of 470 women in the placebo group (58.3%).

A live baby was born after the 34th week of pregnancy to 37.4% of women (176 out of 470) on levothyroxine compared to 37.9% (178 out of 470 women) in the placebo group (relative risk [RR] 0.97; 95% confidence interval [CI] 0.83–1.14; absolute risk difference 0.4%; 95% CI –6.6 to 5.8).

A serious adverse event occurred in 28 women on levothyroxine (5.9%) and 18 women in the placebo group (3.8%; p = 0.14).

No significant differences were observed even after considering the individual subgroups and analyzing secondary parameters.

Conclusion and Discussion

The study did not confirm the effect of levothyroxine on the number of live births after the 34th week of pregnancy in women with thyroid peroxidase antibodies. However, it was limited by the fact that all patients took levothyroxine at a dose of 50 µg/day. It cannot be ruled out that adjusting the dose based on patient weight, thyroid antibody concentration, and TSH might yield different results.

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Source: Dhillon-Smith R. K., Middleton L. J., Sunner K. K. et al. Levothyroxine in women with thyroid peroxidase antibodies before conception. N Engl J Med 2019; 380: 1316–1325, doi: 10.1056/-NEJMoa1812537.