Levothyroxine No Boon for Birth Rates in Women With Possible Thyroid Disorder

According to the Phase III T4LIFE trial, levothyroxine treatment failed to promote pregnancy outcomes in women who were positive for thyroid peroxidase antibodies (TPO-Ab) but had normal thyroid function.

Among 187 women with recurrent pregnancy loss trying to conceive, once-daily levothyroxine did not result in a higher rate of live births – the primary outcome of the study – versus placebo (50% versus 48% for placebo), RR 1.03 , 95% CI 0.77–1.38), reported by Mariette Godijn, MD, PhD, of the University of Amsterdam in the Netherlands, and colleagues Lancet Diabetes and Endocrinology,

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

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

“Based on our findings, we do not recommend routine use of levothyroxine in women with recurrent pregnancy loss who have normal thyroid function and are positive for TPO-Ab,” Godijn’s group wrote.

These results were not as surprising, 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. History of pregnancy loss or infertility and in them using in-vitro fertilization,

They reported that women positive for thyroid peroxidase antibodies have a higher risk of pregnancy loss. Antibody positivity has also been associated with other complications, including unexplained subfertility, premature birth, and postpartum thyroiditis. A leading hypothesis for this connection 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 because of a lack of high-quality evidence on the efficacy of levothyroxine treatment in euthyroid women with recurrent pregnancy loss who are TPO-Ab positive,” the researchers said. explained the logic behind their operation. testing.

Subclinical or apparent hypothyroidism may be apparent in early pregnancy due to an increased need for thyroid hormones. In addition, women positive for TPO-Ab have poorer normal physiological thyroidal response to human chorionic gonadotropin in early pregnancy. Because of this, it has been hypothesized that levothyroxine supplementation may reduce the risk of pregnancy complications.

“As expected, the live birth rate among women with repeated pregnancy loss was higher than in women with a history of infertility,” said Godijn’s group, “but in our population and in randomized trials of infertile women, levothyroxine increased did not increase. live birth rate. ,

accompanying commentary Author Tim Korevar, MD, PhD, of the Erasmus University Medical Center in the Netherlands, and Rima Dhillon-Smith, PhD, of the University of Birmingham in the UK, praised the study for providing more definitive evidence on the subject.

“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 pregnancy,” they wrote. “Whether TPO-Abs should be routinely evaluated when screening for hypothyroidism in women at high risk for adverse fertility or obstetric outcomes cannot be determined on the basis of available data, although as TPO-Abs Thyroid function test follow-up in women known to be known seems positive.”

The mechanism by which TPO-Abs contribute to adverse pregnancy outcomes does not appear to be entirely through thyroid dysfunction, noted Korewar and Dhillon-Smith, suggesting that future studies may address this question. and examine alternative therapies, such as immunosuppressants, to find out.

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

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

A main limitation of the study was the small sample size due to the low prevalence of eligible participants. The researchers intended to enroll more than 200 patients, but slow recruitment forced them to formally stop the trial after enrolling 187 women.

“With this sample size we are not able to fully account for dropout, and the estimates have broad 95% CIs,” Godijn’s group said. “To detect a 5% difference in the live birth rate would need to include more than 3,000 women.”

  • Jeff Minradt is a freelance medicine and science writer based in Rochester, NY.


This study was supported by the Dutch Organization for Health Research and Development, Fonds Natsohra, the Dutch Patient Organization for Thyroid Disorders, Jan Dekker Stichting and Dr. Ludgaardin Baumannstiching.

Goddijn and co-authors reported relationships with Guerbet, Merck and Ferring.

Korevar and Dhillon-Smith reported relationships with Berlin-Chemie, Goodlife Healthcare, EXCEMED, Merck, IBSA, Quiddell and the American Thyroid Association’s guideline committee.

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