Thyroid Disease in Pregnancy: A Touch of Clarity

Diagnosing and treating thyroid disease during pregnancy are complex. For diagnosis, knowledge of changes in thyroid hormone levels during pregnancy in general, and by trimester in specific, is core to accurate diagnosis. Adding to the complexity is the evolution over the past decade in the definition of what constitutes a normal first trimester thyrotropin (TSH). Despite widespread agreement that TSH normative values are best determined locally, these data rarely exist. In its absence, normative values have been developed by the American Thyroid Association and published in the thyroid and pregnancy guidelines.

The first iteration of the guidelines, published in 2011, defined the first trimester TSH upper limit of normal (ULN) as 2.5 mU/L (1). Newer guidelines, published in 2017, revised the ULN to 4.0 mU/L (2). Nevertheless, subsequent epidemiological studies continue to show a wide range of ULN values, leaving the basic question of what constitutes the “true” TSH ULN in the first trimester as unresolved.

Treating thyroid disease during pregnancy is similarly complex, although for different reasons. Unanimity exists regarding the need to treat overt thyroid disease during pregnancy, be it overt hypothyroidism or overt hyperthyroidism. Similarly, there is consensus that subclinical hyperthyroidism does not require intervention, although recent studies suggest that subclinical hyperthyroidism may not be quite as benign as once thought. However, controversy and confusion exist whether or not, and under what circumstances, subclinical hypothyroidism (SCH) requires levothyroxine (LT4) intervention.

To place the controversy in perspective, SCH has been associated with miscarriage, gestational hypertension, gestational diabetes, preterm delivery (PTD), neonatal intensive care admission, and neonatal death. However, two large multicenter studies demonstrated no benefit of LT4 in women with SCH on the IQ of their unborn children (3,4). However, major limitations of both trials are that LT4 was not initiated until the second trimester.

One need only look at the disparate recommendations of medical societies to appreciate the present state of confusion. At polar opposites are the Italian Thyroid Association (ITA) (5) and the American College of Obstetricians and Gynecologists (ACOG) (6). The ITA recommends that all pregnant women with SCH be treated, while ACOG only recommends LT4 intervention for pregnant women with overt hypothyroidism.

In between, the ATA 2017 guidelines present a nuanced but somewhat complex approach (2). Specifically, ATA guidelines recommend LT4 intervention in the first trimester for thyroid peroxidase antibody positive (TPO-Ab+) women with a TSH level between 4.0 and 10.0 mU/L and that LT4 may be considered in thyroid antibody negative (TAb)− women with TSH levels between 4.0 and 10.0 mU/L.

The obvious question is why does such disparate recommendations exist among medical societies? Clarity will only come from new data. It is in this context that we examine the article by Chen et al. in this issue of Thyroid (7). Chen et al. performed a historical cohort analysis assessing the impact of LT4 therapy (LT4 Rx) initiated before eight weeks gestation on the intellectual development of the offspring of women with thyroid peroxidase antibody negative (TPO-Ab−) SCH. The five groups in the study were (1) TSH between 2.5 and 4.0 mU/L with LT4 Rx, (2) TSH between 4.0 and 10.0 mU/L with LT4 Rx, (3) TSH between 2.5 and 10.0 mU/L with no LT4 Rx, (4) TSH between 4.0 and 10.0 with no LT4 Rx mU/L, and (5) TSH <2.5 mU/L and no LT4 Rx (control group).

The outcome variable was the development quotient (DQ) on the Gessell Development Diagnosis Scale measured in the offspring at age two years. The major finding of the study was a significant decrease in DQ in women with TSH levels between 4.0 and 10.0 mU/L who were not treated with LT4 versus the control group. In contrast, LT4-treated women with TSH levels between 4.0 and 10.0 had offspring with DQ values similar to controls. Limitations of the study, as acknowledged by the authors, include its retrospective design and performance in a single center.

How should the study by Chen et al. impact future ATA thyroid and pregnancy guidelines? To answer that question, research published subsequent to 2017 should be assessed. Although there have been numerous publications and editorials since 2017, the 2018 article by Nazarpour et al. is particularly germane (8). In their prospective trial, 254 pregnant TPO-Ab− women with SCH (defined as a TSH between 4 and 10 mU/L) were randomized to either receive (n = 176) or not receive (n = 178) LT4 Rx. The mean gestational age at the first visit in the trial was 11.4 weeks. The rate of PTD was compared with a control group of 940 pregnant women who were euthyroid and TPO-Ab−.

A statistically significant decline in the percentage of PTD was found in the SCH TPO-Ab− LT4-treated group when compared with the SCH TPO-Ab− untreated group (7.3% vs. 19.0%, p = 0.04). There was no statistically significant difference in the PTD group between the controls and SCH TPO-Ab− treated groups (5.6% vs. 7.3%). The number of TPO-Ab− women with SCH needed to treat to prevent PTD was 3.8.

In summary, since the publication of the 2017 ATA guidelines, 2 studies, 1 prospective (8), and now 1 retrospective (7) have demonstrated a statistically significant decrease in adverse events when LT4 is administered early during pregnancy to TPO-Ab− women with SCH (TSH between 4.0 and 10.0 mU/L). Based on these two studies, I believe there is sufficient evidence now to support recommending LT4 therapy for all first trimester pregnant women with SCH (TSH between 4 and 10 mU/L), irrespective of whether they are TPO-Ab+ or TPO-Ab−. Women who meet these criteria comprise 4.1% of all pregnant women in the United States (9) or ∼147,000 women. The implications for universal screening for thyroid disease during pregnancy are obvious.