Levothyroxine for the Treatment of Subclinical Hypothyroidism in Thyroperoxidase Antibody Negative Pregnant Women: The Jury Is Still Out

Overt hypothyroidism in pregnancy is known to be associated with adverse obstetric and child developmental effects, and there is universal agreement that it requires treatment with levothyroxine (LT4). Observational cohort studies have demonstrated that gestational subclinical hypothyroidism is associated with adverse obstetric outcomes, although the evidence demonstrating a benefit of LT4 treatment in subclinical hypothyroidism during pregnancy is limited. Two large randomized clinical trials in which LT4 was initiated in the second trimester failed to demonstrate effects on child cognition or on obstetric outcomes (1,2).

A recent retrospective study of 127 mother–child pairs by Chen et al. assessed subclinically hypothyroid (TSH 4.0–10.0 mIU/L), thyroperoxidase antibody (TPOAb) negative pregnant women, some of whom had elected to receive LT4 treatment during gestation (3). At 2 years of age, developmental scores in children of the untreated mothers (n = 28) were lower than those of children whose mothers had been euthyroid during gestation (n = 27); child developmental scores in the treated group (n = 26) did not differ from the group of euthyroid control children.

Strengths of this study included the inclusion of participants before eight gestational weeks and blinding of child examiners to maternal treatment status. However, this study has multiple important limitations. It was unrandomized. Primary analyses were not adjusted for potential confounders. The lack of significant differences across measured baseline parameters in this small sample does not exclude the possibility of confounding (e.g., women who opted for LT4 treatment were better educated than those who did not). Rates of dropout due to a switch in initial treatment intentions (start of LT4 later in pregnancy), nonadherence, other undisclosed reasons or loss to follow-up were very high (65% of treated women and 74% of those without treatment) and may have led to bias. The study was small (26–28 mother–child pairs per arm) and no power calculation was performed before the start of the study. As acknowledged by the authors, adequately powered prospective randomized trials will be needed to truly understand whether initiation of LT4 treatment for TPOAb negative, subclinically hypothyroid women early in gestation improves child developmental outcomes.

Based on the study by Chen et al. and a small randomized clinical trial published in 2018 by Nazarpour et al. (4), the commentary by Stagnaro-Green, which accompanied the Chen et al. study, calls for recommending LT4 treatment for all first-trimester pregnant women with serum TSH >4 mIU/L, regardless of TPO Ab status, and effectively calls for universal serum thyroid function screening of pregnant women (5). We believe that this is premature. The study by Chen is hypothesis-generating, but in light of its methodological limitations it should not be used as a rationale for expanding treatment recommendations.

The Nazarpour trial had a more rigorous study design, but its primary analysis showed no difference in rates of preterm delivery among TPOAb negative women with serum TSH 2.5–10.0 mIU/L who were randomized to LT4 treatment starting at 11 weeks’ gestation and control women who did not receive treatment. A secondary analysis did show a reduction in preterm delivery in treated women versus controls when the sample was restricted to those women whose serum TSH level was >4.0 mIU/L at baseline.

We agree that it will be important to rigorously evaluate the new data that have been published in the 5 years since the American Thyroid Association (ATA)'s most recent thyroid in pregnancy guideline. Over the past two decades there has been a rapid evolution in clinical practice guideline methodology. The ATA is committed to a stringent process that includes transparency about guideline methods, the use of commissioned systematic reviews to inform recommendations, and the use of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system for rating the strength of recommendations and the quality of the body of evidence used to inform them (6).

A new international multidisciplinary ATA thyroid in pregnancy guideline task force has been convened (chaired by Drs. Korevaar and Leung) and has recently started its work. The task force includes representatives from multiple stakeholders (including sister endocrine societies, obstetric societies, primary care clinicians, and patient representatives). It is anticipated that an updated guideline will be published in early 2024. Among other questions, the upcoming updated guidelines will re-evaluate the totality of evidence for and against treatment of TPOAb negative pregnant women with serum TSH concentrations in the 4–10 mIU/L range.