TPO-Antibody Positivity Often Falls Below Assay Cutoffs in Pregnancy

Nancy A Melville

September 29, 2016

DENVER – Thyroid peroxidase (TPO) antibodies at concentrations well below those used by assay manufacturers to indicate positivity are associated with compromised maternal thyroid function during pregnancy, potentially underestimating the number of women with clinically relevant thyroid autoimmunity, according to new research.

"We found that up to 29% of women with TPO antibodies below the assay cutoffs for positivity actually already have higher thyroid-stimulating hormone [TSH] concentrations, so we may be missing these women who may have thyroid autoimmunity to the extent that it changes thyroid function during pregnancy," first author Tim Korevaar, MD, from Erasmus University Medical Center in Rotterdam, the Netherlands, said in presenting the findings here the American Thyroid Association (ATA) 2016 Annual Meeting.

Approximately 5.6% to 22.1% of women are reportedly TPO-antibody positive, and recent research has shown that women with subclinical hypothyroidism in pregnancy are at a greater risk for complications if they are TPO-antibody positive.

New ATA guidelines, due to be published later this year, are in fact expected to recommend that treatment of subclinical hypothyroidism in pregnancy can be considered for those with TSH concentrations above a pregnancy-specific TSH cutoff or a fixed cutoff of 4.0 mIU/L, unless patients are TPO-antibody positive, in which case the limit is lower, at just 2.5 mIU/L, Dr Korevaar noted.

"What this means is that for all women with TSH concentrations between 2.5 and 4 mIU/L, the decision of whether treatment should be considered will really depend on the presence of TPO-antibody positivity," explained Dr Korevaar.

An important challenge, however, is that definitions of TPO-antibody positivity vary significantly according to the assay manufacturer — from as low as 15 up to 143 IU/L.

Alex Stagnaro-Green, MD, regional dean of the University of Illinois College of Medicine at Rockford, IL, who comoderated the session, commented that Dr Korevaar's study provided intriguing insights on the understanding of TPO antibodies in pregnancy.

"I thought that was an important study with important implications," he told Medscape Medical News.

"It was interesting that [TPO] levels in at least two of the three cohorts on the manufacturers' cutoffs wouldn't be considered antibody positive, but physiologically, it does seem they are positive in terms of thyroid function.

"It shows the power of having very large databases and [prompts] us rethink how we define someone who is TPO antibody positive."

Evaluating TPO Positivity in Pregnancy

In an effort to establish an improved specificity for TPO-antibody positivity, Dr Korevaar and his colleagues evaluated data on patients from three large population cohorts: the Generation R Study of 5563 women less than 18 weeks pregnant, with data from 2002 to 2006; the ABCD study of 4079 women less than 20 weeks pregnant, with data from 2002 to 2006; and the HAPPY trial of 2102 women less than 20 weeks pregnant and 1712 women 31 to 35 weeks pregnant, with data from 2013 to 2014.

After exclusions for factors such as preexisting thyroid disease, medication, or fertility treatment, the total study population was 11,212 women.

The manufacturer-defined TPO-antibody concentrations of positivity ranged from >35 IU/L in the HAPPY study to >60 IU/L in the Generation R cohort and >80 IU/L in the ABCD trial; however, the results from the studies showed TSH concentrations became higher starting at TPO antibodies of 34 IU/L, 25.7 IU/L, and 30.7 IU/L in the three trials.

Similar numbers corresponded to lower FT4 concentrations.

"From a population perspective, these cutoffs were highly similar and occurred from the 92nd percentile," Dr Korevaar told Medscape Medical News.

A comparison of those population percentiles with the assay manufacturer cutoffs showed important differences, with up to 29% of women having higher TSH concentrations at TPO-antibody concentrations below manufacturer cutoffs.

As many as 23% to 25% who were below the cutoff levels showed TSH concentrations in the 2.5–4.0-mIU/L range, which may make them candidates for treatment in pregnancy.

Importantly, the association of TPO-antibody concentrations with higher TSH concentrations, as well as with lower FT4 concentrations, were statistically significant only during early pregnancy (both P < .001).

The findings are consistent with previous research showing that TPO antibodies may lower the thyroidal stimulation by hCG during pregnancy (presented earlier this month by Dr Korevaar and his team at the European Thyroid Association meeting in Copenhagen).

In later pregnancy, when hCG concentrations are much lower, the association between TPO-antibody concentration and TSH was attenuated by as much as 60%, and no clear threshold for TPO antibodies could be identified.

Similarly, no association was seen in late pregnancy between TPO-antibody concentrations and FT4.

The findings underscore the need to consider unique pregnancy changes in TPO-antibody concentration assessment, Dr Korevaar said.

"For our study it is important that the assay cutoffs are not derived from pregnant populations, [because] during pregnancy thyroid physiology changes," he said.

"The latter is the reason that guidelines advocate the use of pregnancy-specific reference ranges for TSH and FT4, but the guidelines have no recommendations for TPO antibodies."

Further Research Needed: Consortium on Thyroid and Pregnancy

Dr Korevaar added that further research is needed to better clarify TPO-antibody cutoffs that are meaningful in clinical practice in pregnancy.

"Larger studies encompassing more commonly used TPO-antibody assays are needed to provide cutoffs for clinically relevant TPO-antibody concentrations and also assess when TPO antibodies become a risk factor for adverse outcomes," he said.

With the need for large numbers and collaboration, Dr Korevaar's team at Erasmus University in Rotterdam and a group at Cardiff University in Wales have founded the Consortium on Thyroid and Pregnancy.

"This consortium aims to study data gaps on thresholds for disease and thyroid disruption during pregnancy, and currently 23 studies are included with data on over 80,000 subjects worldwide," Dr Korevaar noted.

Dr Korevaar and Dr Stagnaro-Green had no relevant financial relationships.

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American Thyroid Association (ATA) 2016 Annual Meeting; September 23, 2016; Denver, Colorado.

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