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Levothyroxine treatment failed to boost pregnancy outcomes in women who were positive for thyroid peroxidase antibodies (TPO-Ab) but had normal thyroid function, according to a phase III T4LIFE trial.

Among 187 women with recurrent pregnancy loss trying to conceive, once-daily levothyroxine didn't result in a significantly higher rate of live births -- the study's primary outcome -- versus placebo (50% vs 48% for placebo, RR 1.03, 95% CI 0.77-1.38), Mariëtte Goddijn, MD, PhD, of the University of Amsterdam in the Netherlands, and colleagues reported in .

There were also no significant differences between the treatment and placebo group for any of the following secondary outcomes:

• Pregnancy loss at <20 weeks: 23% versus 33% (RR 0.71, 95% CI 0.41-1.21)
• Ongoing pregnancy rates: 68% versus 63% (RR 1.08, 95% CI 0.85-1.37)
• Preterm birth at <37 weeks: 6% versus 4% (RR 1.41, 95% CI 0.33-6.08)

"On the basis of our findings, we do not advise routine use of levothyroxine in women with recurrent pregnancy loss who have normal thyroid function and are positive for TPO-Ab," Goddijn's group wrote.

These results didn't come as much of a surprise, as they were in line with previous trial findings that studied the effect of levothyroxine on live birth rates in women who are TPO-Ab positive with a and in those .

Women positive for thyroid peroxidase antibodies have a higher risk of pregnancy loss, they pointed out. Antibody positivity is also linked with other complications, including unexplained subfertility, preterm birth, and postpartum thyroiditis. A leading hypothesis for this association is that these women have a chronic lymphocytic thyroiditis that has not yet led to hypothyroidism.

"We are faced with conflicting recommendations from international guidelines due to a scarcity of high-quality evidence on the efficacy of levothyroxine treatment in euthyroid women who are TPO-Ab positive with recurrent pregnancy loss," the researchers stated when explaining the reasoning behind conducting their trial.

Subclinical or overt hypothyroidism can become apparent in early pregnancy because of the increased need for thyroid hormone. Furthermore, women positive for TPO-Ab have an impaired normal physiological thyroidal response to human chorionic gonadotropin in early pregnancy. Because of this, it's been hypothesized that levothyroxine supplementation could reduce the risk of pregnancy complications.

"As expected, the live birth rate in women with recurrent pregnancy loss was higher than in women with a history of infertility," Goddijn's group added, "but both in our population and in randomised trials of infertile women, levothyroxine did not appear to increase live birth rates."

authors Tim Korevaar, MD, PhD, of the Erasmus University Medical Center in The Netherlands, and Rima Dhillon-Smith, PhD, of the University of Birmingham in the U.K., praised the study for providing more definitive evidence on this topic.

"This study suggests that there is no routine place for levothyroxine treatment in euthyroid women who are TPO-Ab positive who are actively trying for a pregnancy," they wrote. "Whether TPO-Abs should be assessed routinely when screening for hypothyroidism in women at high risk for adverse fertility or obstetric outcomes cannot be determined on the basis of the available data, although thyroid function test follow-up in women known to be TPO-Ab positive seems warranted."

The mechanism by which TPO-Abs contribute to adverse pregnancy outcomes does not appear to be solely through thyroid dysfunction, Korevaar and Dhillon-Smith noted, suggesting that instead, future studies test alternative therapies, such as immunosuppressants, to further explore this question.

This double-blind trial took place across 13 secondary and tertiary hospitals in the Netherlands, Belgium, and Denmark. Participants were women age 18 to 42 who were TPO-Ab positive, had two or more pregnancy losses, and had a thyroid stimulating hormone (TSH) concentration within the institutional reference range.

The 187 participants were randomized 1:1 to receive oral levothyroxine or placebo once per day. The dose of levothyroxine was based on preconception TSH concentrations, ranging from 0.5 to 1.0 μg/kg of body weight. Levothyroxine or placebo was continued until the end of pregnancy.

A chief limitation of the study was the small sample size, due to the low prevalence of eligible participants. Researchers intended to enroll more than 200 patients, but slow recruitment forced them to formally stop the trial once 187 women had been enrolled.

"With this sample size we are not able to fully account for dropouts, and the estimates have wide 95% CIs," Goddijn's group said. "Detection of a difference of 5% in live birth rate would require inclusion of more than 3,000 women."

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