according to a prospective observational study published in the Journal of Clinical Endocrinology & Metabolism.
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Whether asymptomatic patients should be screened for mild subclinical hypothyroidism (SCH) or thyroid peroxidase antibodies (TPOAb) remains an open question, however. “In the absence of evidence of benefit with LT4 [levothyroxine] treatment and possible suggestion of harm ... we pose the question of whether screening should be performed at all in asymptomatic individuals,” wrote Rima K. Dhillon-Smith, MBChB, PhD, of the University of Birmingham (England), and colleagues. “Large randomized trials are needed to establish if preconception LT4 treatment of mild SCH with or without TPOAb positivity is beneficial. If treatment is found to be beneficial, this study presents the prevalence of thyroid disorders that can be expected.”
Subclinical hypothyroidism may represent an early stage of thyroid dysfunction. The condition has been associated with subfertility, miscarriage, preterm birth, preeclampsia, and perinatal mortality. Thyroid peroxidase antibodies also have been associated with adverse pregnancy outcomes, and their presence increases the risk of subclinical and overt thyroid disease in pregnancy. “There is international agreement on the treatment of overt thyroid disease,” the researchers wrote. “However, the treatment strategies for SCH or TPOAb preconception and antenatally are debated.”
The Thyroid Antibodies and Levothyroxine (TABLET) trial, to which the present study was linked, “found no improvement in live birth or any secondary pregnancy or neonatal outcomes in euthyroid women with TPOAb taking 50 mcg of LT4, compared with placebo.”
To examine various thyroid-stimulating hormone (TSH) cutoff levels for diagnosing subclinical thyroid disease in preconception asymptomatic women with a history of miscarriage or subfertility, Dr. Dhillon-Smith and colleagues conducted a prospective, observational cohort study at 49 hospitals in the United Kingdom. The study included more than 19,200 patients between November 2011 and January 2016. Participants were aged 16-41 years, had a history of miscarriage or subfertility, and were actively trying to get pregnant.
Using accepted reference ranges, the investigators identified undiagnosed overt hypothyroidism in 0.2%, overt hyperthyroidism in 0.3%, severe SCH (TSH greater than 10 mIU/L) in 0.2%, and SCH (TSH greater than 4.5 mIU/L) in 2.4%. “Lowering the upper limit of TSH to 2.5 mIU/L, as is the recommendation by international societies for ‘high-risk’ women,” such as those with recurrent pregnancy loss or those undergoing assisted reproductive technology, “would class 16%-20% of women as subclinically hypothyroid,” the authors reported.
The prevalence of TPOAb was 9.5%, and the presence of these antibodies “was the factor associated most significantly with any degree of thyroid dysfunction, after adjustment for confounders,” Dr. Dhillon-Smith and colleagues wrote. Multiple regression analyses found that the likelihood of subclinical hypothyroidism (TSH greater than 4.5 mIU/L) was increased for participants with a body mass index of 35 kg/m2 or greater (adjusted odds ratio, 1.71) and Asian ethnicity (aOR, 1.76).
The U.K. rates of thyroid dysfunction appear to be lower than rates in the United States, and it is unclear why higher body mass index and Asian ethnicity were independently associated with higher TSH concentrations, commented Mark P. Trolice, MD, director of Fertility CARE: The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.
Women with a history of three or more miscarriages or subfertility were not more likely to be TPOAb positive, compared with women with one or two previous miscarriages, which “underscores the evidence that a recurrent pregnancy loss evaluation yields similar diagnostic findings at two versus three or more losses,” Dr. Trolice said.
According to the American Society for Reproductive Medicine, it is reasonable to test infertile women trying to conceive and to treat SCH with levothyroxine to maintain a TSH within the normal range. Women who have TSH greater than 2.5 mIU/L and/or are TPOAb positive can be considered for treatment with levothyroxine.
The Endocrine Society recommends levothyroxine treatment in women with SCH, especially if they are TPOAb positive.
An American Thyroid Association guideline recommends that subclinically hypothyroid women undergoing in vitro fertilization or intracytoplasmic sperm injection be treated with levothyroxine. A 2019 Cochrane Database review, however, found that low-quality evidence precludes clear conclusions.
“While thyroid autoimmunity has been associated with increased miscarriage, preterm births, and lower live birth rates, the confusion lies in which preconception women to test, when to obtain testing, and how to manage nonovert thyroid disease,” said Dr. Trolice, who is a member of the Ob.Gyn. News editorial advisory board.
The observational study was linked to the TABLET trial, which was funded by the National Institute for Health Research. The researchers had no relevant conflicts of interest.
SOURCE: Dhillon-Smith RK et al. J Clin Endocrinol Metab. 2020 Jun 17. doi: 10.1210/clinem/dgaa302.