T4 Doesn't Prevent Miscarriages in Antibody-Positive Women

Miriam E. Tucker

March 23, 2019

NEW ORLEANS — Giving levothyroxine before conception to women with normal thyroid function but who have thyroid peroxidase (TPO) antibodies did not reduce the rate of miscarriage among those who became pregnant, new research shows. 

The findings were presented March 23 here at ENDO 2019: The Endocrine Society Annual Meeting by Rima K. Dhillon‑Smith, MB, ChB, PhD, clinical lecturer at the University of Birmingham, UK, and simultaneously published in the New England Journal of Medicine.

"TPO antibodies are found in the blood in approximately one in 10 women who have normal thyroid function, and they have been linked to increased risk of miscarriage and preterm birth," Dhillon-Smith explained, adding that the presence of the antibodies is associated with an approximate fourfold increased risk for miscarriage.

Meanwhile studies examining the use of levothyroxine during pregnancy, including some employing assisted reproductive technologies, in women with TPO antibodies and normal thyroid function have shown mixed results.

The current study was a double-blind, placebo-controlled randomized trial involving nearly 1000 women with a history of miscarriage who were euthyroid but positive for TPO antibodies.

There were no differences in rates of live births between those given levothyroxine 50 μg once daily or placebo prior to conception through the end of pregnancy. There were also no differences in secondary outcomes including pregnancy loss, preterm birth, or neonatal outcomes.

"It's a little bit disappointing in the sense that there's no benefit, but it's really important because it tells us that we really shouldn't be using thyroxine for these women, and that we shouldn't be giving them false hope in saying there is a benefit," Dhillon‑Smith told Medscape Medical News in an interview. 

And, she noted during her presentation, the findings also call into question the whole practice of thyroid antibody testing in pregnant women with prior miscarriages or infertility.

"One of the prerequisites for a screening test is you need to have a treatment or intervention which modifies the outcome and at present for this population we don't have that, so are we actually just generating anxiety rather than helping them?"

Asked to comment, session comoderator Licy L. Yanes Cardozo, MD, assistant professor of medicine at the University of Mississippi Medical Center, Jackson, told Medscape Medical News, "It was a great study. It was a randomized, very large clinical trial, very powerful, with many patients...We have to keep in mind that the target of the treatment was the [thyroid stimulating hormone]. They really didn't intervene with lowering the level of TPO antibodies, which is the one associated with miscarriage."

Indeed, session comoderator Michael T. McDermott, MD, professor of medicine and clinical pharmacy and Endocrinology and Diabetes Practice director at the University of Colorado, Aurora, explained that in healthy pregnancies, women increase their thyroid hormone production by 30% to 50% to supply the fetus, and the presence of TPO antibodies interferes with that production.

But if the mechanism involves the antibodies themselves, then an effective intervention may need to target the antibodies. "We don't know the mechanism of the miscarriages so maybe we haven't targeted the right thing," he said.   

No Differences in Pregnancy Outcomes, Plus Hints of Harm

In their article, Dhillon‑Smith and colleagues note that the 2017 American Thyroid Association (ATA) guidelines say administration of levothyroxine to TPO antibody-positive euthyroid women with a history of pregnancy loss may be considered "given its potential benefits in comparison with its minimal risk."

Indeed, "the guideline task force drew attention to our ongoing trial," the Thyroid Antibodies and Levothyroxine (TABLET) trial, they add.

And in the UK currently, a survey of fertility clinicians has shown that almost 40% said they routinely use levothyroxine in women with TPO antibodies to reduce miscarriage and pre-term birth, Dhillon-Smith and colleagues say in a press release issued by the University of Birmingham.

Now the results of the TABLET study are in. The trial was conducted in 952 women who were trying to conceive and had a history of miscarriages or infertility, were biochemically euthyroid (TSH within specified reference ranges), and were TPO antibody positive. Of the 476 participants, 266 women randomized to levothyroxine and 274 women randomized placebo became pregnant.

The proportion with a live birth at 34 weeks or later was nearly identical: 37.4% of the levothyroxine group versus 37.9% given placebo (P = .74).

Secondary outcomes among those who became pregnant didn't differ either between the levothyroxine and placebo groups, including the proportion with miscarriages (28.2% vs 29.6%; P = .95) or live birth at less than 34 weeks (3.8% vs 3.6%; P = 1.02). And neonatal outcomes, such as birth weight or Apgar scores at 1 or 5 minutes, were similar between the two groups.

The proportion of women who withdrew from the study because of abnormal thyroid function tests did not differ between the levothyroxine and placebo groups (9.8% vs 9.6%).

However, the proportion with pre-eclampsia (5% vs 3%) and gestational diabetes (11% vs 9%) were higher among those in the levothyroxine-treated group, although the difference was not significant. 

No Evidence of Benefit so Change the Guidelines 

Cardozo agreed the results further support the advice not to prescribe levothyroxine for these patients. "Although this wasn't significant, it's still a concern. There are no benefits, and it could be harmful."

McDermott said, "I'm not convinced of the harm, but we shouldn't use it if it's not doing anything."

Coauthor of TABLET Kristien Boelaert, MD, also of the University of Birmingham, agreed, stressing in her institution's press release: "We...hope that the current practice of routine testing of TPO antibodies in high-risk populations such as women with miscarriage and reduced fertility is reconsidered."

She added: "We hope that national and international guidelines are updated to remove current recommendations which advise consideration of the use of levothyroxine in these women."

What About Targeting the Antibodies?

Dhillon‑Smith acknowledged that there is some support for the idea of targeting the TPO antibodies based on the hypothesis that the miscarriages result from a generalized autoimmune imbalance. Some have suggested use of intravenous immune globulin or steroids, while a current trial is investigating the use of selenium supplementation in autoimmune thyroiditis, although not during pregnancy.  

McDermott noted such a trial might be difficult to conduct in pregnant women. "Giving anything to pregnant women is difficult to get approved, although selenium is an over-the-counter supplement. You could give it to nonpregnant women with positive TPO antibodies. There's very little risk in that. But in pregnancy, we don't know the risk. Giving it preconception until they become pregnant might be less of an ethical issue."

Meanwhile, Dhillon-Smith says one of her team's next steps will be to see if preconception levothyroxine supplementation might have a greater impact on pregnancy outcomes among women with subclinical hypothyroidism.

In addition, "We have to go back to thinking about what is the underlying cause, and then think about how we can modify it."

The research was commissioned by the UK National Institute for Health Research. Dhillon-Smith, Cardozo, and McDermott have reported no relevant financial relationships.

ENDO 2019. Presented March 23, 2019. Abstract OR11-1.

N Engl J Med. Published online March 23, 2019. Abstract

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