Thyroid Function Test Abnormalities Linked to Preterm Birth

Nancy A. Melville

August 20, 2019

Thyroid function test abnormalities in pregnancy, including those at subclinical levels, are linked to a higher risk of preterm birth, according to a new meta-analysis. However, there is no evidence, as yet, to indicate that treatment improves outcomes.

"Among pregnant women without overt thyroid disease, subclinical hypothyroidism, isolated hypothyroxinemia, and thyroid peroxidase (TPO)-antibody positivity were significantly associated with higher risk of preterm birth," the authors write in an article published online August 20 in JAMA.

Noting that recent large clinical trials have failed to show benefit from routine screening and thyroid hormone treatment for the abnormalities, the authors of an accompanying editorialpropose a shift in focus.

"It is time to trust the findings of the major clinical trials, move past consideration of screening for and treatment of mild thyroid testing abnormalities detected during pregnancy, and focus instead on determining their physiological context," write Anne R. Cappola, MD, ScM, University of Pennsylvania, Pittsburgh, and Brian Casey, MD, University of Alabama at Birmingham, in their editorial.

David S. Cooper, MD, professor of medicine and radiology, Division of Endocrinology, Diabetes, and Metabolism, Johns Hopkins University School of Medicine, Baltimore, Maryland, who was not involved in the study, agrees that research could turn to causative factors.

"As the authors point out, future research could be focused on why preterm delivery is associated with subclinical hypothyroidism and/or TPO antibody positivity, since it may not be low thyroid hormone levels that are primarily responsible," he told Medscape Medical News.

"Whether additional randomized controlled trials of thyroid hormone therapy, which are very difficult to do and very expensive, will be forthcoming is uncertain," he added.

Consortium Analysis

Preterm birth is the leading direct cause of morbidity and mortality in children under the age of 5 years, and overt hypothyroidism is a well-known risk factor, hence the concern about the less certain role of milder or isolated thyroid abnormalities is warranted.

To take a closer look, the Consortium on Thyroid and Pregnancy – Study Group on Preterm Birth analyzed 19 published and unpublished prospective study cohorts involving 47,045 pregnant women, who were a mean age of 29 years and had a median gestational age at blood sampling of 12.9 weeks.

Importantly, investigators from each cohort provided individual participant data, making the analysis the largest of its kind to date, allowing for a rigorous analysis and the ability to standardize definitions of thyroid function test abnormalities.

"Previous studies have used widely differing definitions of thyroid function test abnormalities, and by gathering the individual participant data, we were able to homogenize these definitions to those currently used," first author Tim I.M. Korevaar, MD, PhD, Academic Center for Thyroid Diseases, Erasmus Medical Center, Rotterdam, the Netherlands, told Medscape Medical News.

Overall, 2357 (5.0%) of the births were preterm, defined as those delivered before 37 weeks' gestational age.

Of the 1234 (3.1%) women with subclinical hypothyroidism (defined as serum thyroid-stimulating hormone [TSH 4-10] mlU/L), the risk of preterm birth was higher compared to those with normal thyroid levels (6.1% vs 5.0%; odds ratio [OR], 1.29; 95% CI, 1.01 - 1.64; P = .03), after adjusting for factors including maternal age, body mass index, ethnicity, smoking, parity, and gestational age at blood sampling.

In addition, the 904 (2.2%) women with isolated hypothyroxinemia, in which free thyroxine (T4) concentrations are low yet serum TSH levels are normal, had an increased risk of preterm birth compared with euthyroid women (7.1% vs 5.0%; OR, 1.46; 95% CI, 1.12 - 1.90; P = .004).

And among 3043 (7.5%) women who were TPO antibody-positive, which is indicative of an autoimmune disorder such as Graves disease, preterm birth risk was higher compared with those who were TPO antibody-negative (6.6% vs 4.9%; OR, 1.33; 95% CI, 1.15 - 1.56; P < .001).

Isolated hypothyroxinemia and TPO antibody-positivity — but not subclinical hypothyroidism — were each also significantly associated with a higher risk of very preterm birth (delivery earlier than 32 weeks) compared to women without isolated hypothyroxinemia or who were TPO antibody-negative (OR, 2.57 and 2.45, respectively; both P < .001).

The risk of TPO antibody-positivity has previously been shown to be further elevated when TSH levels are above 4.0 mlU/L, and American Thyroid Association guidelines currently recommend the use of different TSH cutoffs in TPO-positive pregnant women.

"These results support the concept of measuring TPO antibodies in women with a TSH above 4 mlU/L and follow-up of women known to be TPO antibody-positive preconception," Korevaar said.

Furthermore, "our results showing that isolated hypothyroxinemia is a risk factor for very preterm birth is an argument that can be used in weighing the harms and benefits of levothyroxine treatment during clinical decision-making for each individual patient. But on its own, cannot validate universal thyroid function screening or levothyroxine treatment," he added.

The editorialists also suggest the data do not support universal screening. They note that among the 47,045 women in the analysis, assuming early screening and treatment would reverse the risk — which is not proven — screening with the three thyroid blood tests would have prevented just 87 preterm births.

"Even under these idealized assumptions, these estimates represent a relatively small potential yield given the very large screening effort required," the editorialist write.

The study was supported by a replication studies grant from the Netherlands Organization for Scientific Research. Korevaar has received personal fees from Berlin-Chemie, Goodlife Healthcare, and Quidel. Disclosures for the other authors are listed in the article. The editorial authors and Cooper have reported no relevant financial relationships.

JAMA. Published online August 20, 2019. Abstract, Editorial

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