BACKGROUND
Hyperthyroidism (overactive thyroid gland) with high thyroid hormone levels and a low TSH can cause problems in pregnancy, such as miscarriage, premature delivery, and high blood pressure in mothers, and problem with baby’s growth. The most common cause of hyperthyroidism in pregnancy is Graves’ disease, where high levels of thyroid stimulating hormone (TSH)-receptor antibody (TRAb) cause thyroid gland to make too much thyroid hormone. Since low TSH levels can occur in normal pregnancy from the effect of high levels of human chorionic gonadotropins (hCG) made by placenta, it is sometimes difficult to tell apart normal transient low TSH levels from Graves’ disease in pregnant women. It is important to distinguish between the two conditions because Graves’ disease may need treatment to prevent problems during pregnancy, but transient low TSH levels do not.

A key part of the diagnosis depends on the presence of TRAb levels. An undetectable TRAb level effectively rules out Graves’ disease. A detectable but low TRAb level can also be normal while an increased level is diagnostic of Graves’ disease. However, it is unclear how TRAb levels change during pregnancy, or even if they change. The cutoff of positive TRAb levels is also different in different laboratories using different assays.

It is important to have a good cutoff for TRAb levels in pregnancy to distinguish diagnoses of Graves’ disease in pregnancy from low TSH level in normal pregnancy, because only Graves’ disease may need treatment. The researchers of this paper studied how often TRAb levels were elevated and how often they were associated with low TSH levels, using a stored blood sample from a large database of pregnant women in Denmark.

THE FULL ARTICLE TITLE
Udall Torp NM et al 2022 TSH-receptor antibodies in early pregnancy. J Clin Endocrinol Metab. Epub 2022 Jun 23. PMID: 35737956.

SUMMARY OF THE STUDY
Patients in this study were selected from 14,323 women in Denmark who had blood samples stored during pregnancy between 2011 and 2015 for a large database. TSH and TRAb levels were measured in the stored blood samples. The hyperthyroid group had 414 women who had TSH level < 0.1mIU/L, suggesting hyperthyroidism. The control group had 524 women who had normal TSH levels between 0.1-2.9mIU/L that were measured before 15 weeks of pregnancy. None of the women in the study had known thyroid disease before pregnancy.

Based on the distribution of TRAb levels in the control group of women, TRAb level of 0.1 IU/L was determined as the cutoff for “positive TRAb” in this study. This was lower than the cutoff recommended by the manufacturer of the assay, which was 1.8 IU/L. Women in the hyperthyroid group were more likely to have positive TRAb levels > 0.1 IU/L compared to women in the control group (6.5% vs 4.6%). When these women were followed for an average of 8 years (ranging from 4-10 years), 52% of women who had TSH < 0.1 mIU/L and TRAb > 1.0 IU/L (positive TRAb) were later diagnosed with hyperthyroidism (24% during pregnancy or within 2 years after delivery), compared to only 8.4% of women who had TSH < 0.1mIU/L and TRAb ≤ 1.0 IU/L (negative TRAb). Among those who had TSH ≥ 0.1mIU/L in control group, less than five women were diagnosed with hyperthyroidism regardless of TRAb levels during the follow up.

A cutoff of > 0.1 IU/L for TRAb levels was generated for pregnant women using a large Danish population data, which was associated with higher likelihood of later diagnosis of hyperthyroidism. In this population, most cases of low TSH in early pregnancy were cases of transiently high levels of thyroid hormone with negative TRAb, with low likelihood of developing hyperthyroidism in the future.

WHAT ARE THE IMPLICATIONS OF THIS STUDY?
This study showed that a low TSH level <0.01 mIU/L in pregnancy was relatively common, occurring in 3.1% of women in this group. This study used a large population of Danish pregnant women with stored blood sample to determine cutoff of TRAb level of 0.1 IU/L as positivity, lower than what was suggested by the manufacturer. Using this cutoff, only 5.1% of women with low TSH had positive TRAb status. Positive TRAb status predicted later development of hyperthyroidism in about half of these women. Since untreated severe hyperthyroidism can have negative impact in pregnancy, it would be important to identify women with hyperthyroidism that need treatment. This study was helpful in assessing a potentially useful cutoff level for TRAb test. However, the clinical application of this result is limited because the study was done only in women in Denmark and using only one assay. The cutoff determined by this study may not be useful in other countries or where other brands of assays for TRAb are used. Given these limitations, it would be important to continue to monitor any pregnant women with low TSH levels in early pregnancy closely to watch for potential development of severe hyperthyroidism that need treatment. Measurement of TRAb levels by any methods would be helpful.

— Sun Y. Lee, MD, MSc

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