August 20, 2019
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Mild maternal thyroid dysfunction increases preterm birth risk

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Pregnant women with mild thyroid dysfunction, such as subclinical hypothyroidism, isolated hypothyroxinemia or thyroid peroxidase antibody positivity, are more likely to deliver preterm when compared with euthyroid women, according to a meta-analysis of 19 cohort studies published in JAMA.

Tim Korevaar

The analysis of individual patient data from more than 47,000 participants, conducted by the Consortium on Thyroid and Pregnancy — Study Group on Preterm Birth, is the largest study of its kind conducted to date, according to researchers, and suggests that subclinical hypothyroidism, isolated hypothyroxinemia and thyroid peroxidase antibody (TPOAb) positivity in pregnant women are risk factors for preterm birth.

“These findings validate a reflex TPOAb measurement for women with a [thyroid-stimulating hormone level] above 4 mU/L and also imply that it is important to actively plan to assess early gestational thyroid function tests in women known to be TPOAb-positive preconception,” Tim Korevaar, MD, PhD, a translational epidemiologist at the Academic Center for Thyroid Diseases at Erasmus Medical Center in Rotterdam, the Netherlands, told Endocrine Today. “Our results showing a higher risk for very preterm birth in TPOAb-positive women, especially when the TSH is above 4 mU/L, seem to echo the current American Thyroid Association guidelines. Our results showing that isolated hypothyroxinemia is a risk factor for both preterm and very preterm birth was most surprising, although further studies are needed to identify the causality of this association.”

Korevaar and colleagues analyzed data from 19 prospective cohort studies conducted through March 2018 with unselected participants with available data on thyroid hormone and TPOAb status, as well as data on gestational age at birth (n = 47,045; mean age, 29 years; median gestational age at blood sampling, 12.9 weeks). Researchers excluded studies in which participants received treatment based on abnormal thyroid function tests. Primary authors provided individual participant data that was analyzed using mixed-effects models.

Thyroid ultrasound female 2019 
Pregnant women with mild thyroid dysfunction, such as subclinical hypothyroidism, isolated hypothyroxinemia or thyroid peroxidase antibody positivity, are more likely to deliver preterm when compared with euthyroid women.
Source: Adobe Stock

Within the cohort, 1,234 women (3.1%) had subclinical hypothyroidism, 904 women (2.2%) had isolated hypothyroxinemia and 3,043 (7.5%) were TPOAb positive. The primary outcome of preterm birth, defined as delivery at less than 37 weeks’ gestational age, occurred in 2,357 women (5%). Very preterm birth occurred in 349 women (0.7%).

Preterm birth risk

In analyses adjusted for maternal age, BMI, race, smoking status, parity, gestational age at blood sampling and fetal sex, women with subclinical hypothyroidism were 29% more likely to deliver preterm vs. euthyroid women (95% CI, 1.01-1.64; absolute risk, 6.1% vs. 5%). Women with isolated hypothyroxinemia were 46% more likely to delivery preterm vs. euthyroid women (95% CI, 1.12-1.9; absolute risk, 7.1% vs. 5%) and women with TPOAb positivity were 33% more likely to deliver preterm vs. women who were TPOAb negative (95% CI, 1.15-1.56; absolute risk, 6.6% vs. 4.9%).

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In prespecified sensitivity analysis, the association between subclinical hypothyroidism and preterm birth was no longer statistically significant after additional adjustment for TPOAb positivity, the researchers wrote.

The researchers noted that the association of TPOAb positivity with preterm birth did not appear to be related to differences in thyroid function, but was modified by the TSH level, exemplified by the higher risk for preterm birth in TPOAb-positive women with a TSH level above 4 mIU/L.

“This study is probably the best evidence that we will have on the association of maternal thyroid function or TPOAb positivity and very preterm birth,” Korevaar said. “This is because very preterm birth is a rare outcome, yet the consequences on child health are enormous.”

Universal screening not justified

In commentary accompanying the study, Anne R. Cappola, MD, ScM, of the division of endocrinology, diabetes and metabolism at the Perelman School of Medicine at the University of Pennsylvania, and Brian M. Casey, MD, of the division of maternal and fetal medicine at the University of Alabama at Birmingham, wrote that the study findings should not be used to justify universal screening of pregnant women.

“Assuming that residual confounding did not affect these estimates and that the links were causal and would be completely reversed by early identification and treatment, how many additional preterm births could be prevented by screening with these three blood tests?” Cappola and colleagues wrote. “Based on this analysis of 47,045 women, an estimated 17 preterm births in those with subclinical hypothyroidism, 21 preterm births in those with isolated hypothyroxinemia and 49 preterm births in [TPOAb]-positive women might have been prevented. Even under these idealized assumptions, these estimates represent a relatively small potential yield given the very large screening effort required, especially when considering contemporary advances in obstetrical and neonatal care in managing late preterm delivery and that only 15% of preterm births in this analysis occurred at less than 32 weeks’ gestational age.”

Cappola and colleagues noted that subclinical hypothyroidism identified during pregnancy may not truly represent thyroid hormone inadequacy, adding, “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.” – by Regina Schaffer

For more information:

Tim Korevaar, MD, PhD, can be reached at the Academic Center for Thyroid Diseases, Erasmus Medical Center, Room Na-2913, Postbus 2040, 3000 CA, Rotterdam, the Netherlands; email: t.korevaar@erasmusmc.nl.

Disclosures: Korevaar reports he received personal fees from Berlin Chemie, Goodlife Healthcare and Quidel. Please see the study for all authors’ relevant financial disclosures. Cappola and Casey report no relevant financial disclosures.