Jury Still Out on Treating Subclinical Hypothyroid in Pregnancy

Kristin Jenkins

January 26, 2017

The first national study in the United States to evaluate the effectiveness and safety of thyroid-hormone therapy for pregnant women with subclinical hypothyroidism shows that treatment can significantly reduce risk of pregnancy loss, but only in patients with higher pretreatment thyroid-stimulating–hormone (TSH) levels.

This suggests that some pregnant patients with subclinical hypothyroidism may be overtreated, says a research team led by Spyridoula Maraka, MD, research collaborator at the Mayo Clinic, and assistant professor at the University of Arkansas for Medical Sciences in Little Rock.

Results of the retrospective US cohort study of 5405 pregnant women with subclinical hypothyroidism — 16% of whom received thyroid-hormone treatment — shows that treatment was associated with a 38% decreased risk of pregnancy loss among women with subclinical hypothyroidism, but this risk reduction was primarily confined to those with pretreatment TSH levels of 4.1 to 10 mIU/L.

Risk of pregnancy loss was not lower among thyroid-hormone treated than untreated pregnant women in those whose pretreatment TSH levels were 2.5 to 4.0 mIU/L, the researchers say in their report published online on January 25 in the BMJ.

The study also reveals an association between thyroid-hormone treatment and an increased risk for gestational diabetes (odds ratio [OR], 1.37 compared with untreated patients), preeclampsia (OR, 1.61), and preterm delivery (OR, 1.60).

"Given the smaller magnitude of effect in the group with TSH concentrations of 2.5 to 4.0 mIU/L and in light of the possible increased risk of other adverse events, treatment may need to be withheld in this group," Dr Maraka and colleagues say.

In a Mayo Clinic press statement, coauthor Juan Brito Campana, MBBS, a Mayo Clinic endocrinologist, says that the association of levothyroxine (Synthroid, AbbVie) therapy with an increased risk of pregnancy-related adverse outcomes should be seen as a preliminary finding and calls for "additional studies evaluating the safety of levothyroxine therapy in pregnant women with subclinical hypothyroidism."

More Research Needed to Refine Information

New guidelines on the treatment of hypothyroidism during pregnancy were recently issued by the American Thyroid Association and were prompted by "a substantial amount of new literature" since the previous guidelines in 2011, task force cochair Elizabeth N Pearce, MD, Boston University School of Medicine, Massachusetts, told Medscape Medical News when these guidelines were published earlier this month

However, she also acknowledged that the management of subclinical hypothyroidism in pregnancy remains controversial and "very unclear based on data. We have provided new process-based recommendations, but I will say the data are still not definitive in that area."

The new ATA guidance raises the TSH level for diagnosis and treatment of subclinical hypothyroidism from 2011 guidelines, Dr Maraka told Medscape Medical News in an email.

This addresses "our previous concern of overdiagnosis and overtreatment in this patient population that led to the decision to conduct this study," she told Medscape Medical News.

Despite this, uncertainty remains, she cautioned.

And while the new ATA guidelines "can help pregnant women and their doctors reach a decision about treatment that will be best," more research is required to "refine the available information," she said.

Still Only 15% of Pregnancies With Subclinical Hypothyroid Treated

For their analysis, Dr Maraka and colleagues looked at the OptumLabs Data Warehouse, a large US administrative claims database that included patients with private insurance as well as those covered by Medicare.

All women aged 18 to 55 years with subclinical hypothyroidism defined as TSH concentration of 2.5 to 10 mIU/L who had a pregnancy visit between January 1, 2010 and December 31, 2014 were included.

A total of 5405 pregnant women with subclinical hypothyroidism were divided into two groups: treated and untreated.

Of the 843 (15.6%) women who started thyroid-hormone treatment, 832 (98.7%) received levothyroxine at a median dose of 50 μg.

Seven patients (0.8%) received thyroid-extract formulation and four patients (0.5%) were treated with a combination of levothyroxine and liothyronine (Cytomel, King Pharmaceuticals). The remaining 4562 (84.4%) women did not receive thyroid hormone.

Each year of the study, the percentage of treated women increased, climbing from 12% in 2010 to 19% in 2014, the researchers note.

And there was a geographic variation in thyroid-hormone prescriptions — the data reveal that significantly more women were receiving treatment in the Northeast and Western regions of the United States than in the Midwest and Southern regions (P < .01).

It's not known how widely recommendations for the treatment of pregnant women with subclinical hypothyroidism have been implemented in the United States.

However, the researchers suggest that full implementation could result in up to 600,000 pregnant women being put on levothyroxine treatment each year, even though there is not enough evidence to show that it improves outcomes.

Still, the fact that less than 16% of this cohort received thyroid hormone in 2014 suggests that clinicians aren't following these recommendations, Dr Maraka and team observe, adding that 1.2% of the treated women in the cohort received thyroid preparations that weren't recommended.

"The cause of this discrepancy is likely multifactorial, including a lack of familiarity with the guidelines among clinicians, paucity of trustworthy evidence to support such recommendations, inconsistencies in practice among endocrinologists, family-medicine physicians, and obstetricians, and nonadherence to levothyroxine by patients," they conclude.

Upper Reference Limit for TSH Has Risen to 4.0 mIU/L

The new 2017 ATA recommendations state that when possible, trimester-specific reference ranges for serum TSH should be defined through assessment of local population data and include only pregnant women with no known thyroid disease, optimal iodine intake, and negative antithyroperoxidase antibody (TPOAb) status.

When local assessments representative of a clinician's practice aren't possible, it is recommended that the lower reference range of TSH be reduced in the first trimester by approximately 0.4 mU/L and the upper reference range reduced by approximately 0.5 mU/L.

This corresponds to a TSH upper reference limit of 4.0 mU/L for the typical patient in early pregnancy.

"This reference limit should generally be applied beginning with the late first trimester, weeks 7 to 12, with a gradual return toward the nonpregnant range in the second and third trimesters," the ATA task force said in its report.

The 2017 guidelines differ in two significant points when compared to 2011 guidelines, Dr Maraka explained.

The first change, for the diagnosis of subclinical hypothyroidism, raises the upper reference limit for serum TSH in the first trimester to ~4.0 mIU/L from 2.5 mIU/L in the previous guidelines.

The second change, in the treatment of subclinical hypothyroidism, recommends treatment in TPO-antibody-positive women with a TSH >4 mIU/L (or greater than the pregnancy-specific reference range if available) and consideration for treatment if TSH is between 2.5 mIU/L and 4 mIU/L.

For TPO-antibody-negative pregnant women, the recommendation for treatment is when the TSH is above 10 mIU/L and treatment may be considered if TSH is between 4.0 and 10 mIU/L.

In 2011, Dr Maraka pointed out, treatment was recommended for pregnant women with subclinical hypothyroidism defined as TSH >2.5 mIU/L who were TPO antibody positive.

Due to insufficient evidence, there was no recommendation for or against universal treatment in TPO-antibody-negative pregnant women with subclinical hypothyroidism at that time, she noted.

Clinicians are encouraged to use a shared decision-making approach to treatment with patients, Dr Maraka said, adding that if treatment is started, monitoring of thyroid function and treatment adjustment "is essential."

Thyroid-Hormone Treatment May Be Needed Only in First Trimester

Dr Maraka also says that the timing of thyroid-hormone treatment is an important area of research and that it may be needed only in the first trimester of pregnancy.

And she stressed that more research is needed to understand whether a causal mechanism exists behind the association of thyroid-hormone treatment and decreased risk for pregnancy loss.

The benefits of thyroid-hormone treatment, specifically in pregnant women with subclinical hypothyroidism who are TPO antibody negative, also need to be evaluated, she said, noting that it has been thought this group carries less risk for pregnancy complications.

In the meantime, results from large randomized trials and the pregnancy complication data from the Controlled Antenatal Thyroid Screening study are expected to provide "more scientific rationale" for management of subclinical hypothyroidism during pregnancy, she concluded.

This study was funded by the Mayo Clinic Robert D and Patricia E Kern Center for the Science of Health Care Delivery. The study authors acknowledged support from the Agency for Healthcare Research and Quality and AcademyHealth but declared no relevant financial relationships.

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BMJ. Published online January 25, 2017. Article

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