Objective: To clarify the association between levothyroxine (LT4) treatment and various adverse pregnancy outcomes in pregnant women with thyrotropin (TSH) levels ranging between 2.5 and 10.0 mIU/L in the first trimester, stratified according to thyroid peroxidase antibody (TPOAb) positivity and TSH level. Methods: This retrospective analysis of retrospectively and prospectively collected cohort data included Chinese pregnant women with TSH levels of 2.5-10 mIU/L and normal free thyroxine levels (11.8-18.4 pmol/L) in the first trimester. All participants were followed up until the completion of pregnancy, and information on LT4 treatment, pregnancy complications, and pregnancy outcomes was recorded. A 1:1 nearest-neighbor propensity score matching (PSM) between the LT4-treated and - untreated groups with a caliper distance of 0.02 was performed using a multivariable logistic regression model. Multivariable-adjusted modified Poisson regression was used to estimate the relative risk (RR) and 95% confidence interval (CI) of LT4 treatment for adverse pregnancy outcomes. Subgroup analyses were also performed in four subgroups simultaneously stratified by TPOAb status (negative or positive) and TSH levels (2.5-4.0 mIU/L as high-normal group and 4.0-10.0 mIU/L as SCH group). The study was registered in the Chinese Clinical Trial Registry (ChiCTR2100047394). Results: Among the 4,370 pregnant women in the study, 1,342 received LT4 treatment and 3,028 did not. The 1:1 PSM yielded 668 pairs of individuals and revealed that LT4 treatment was significantly associated with a decreased risk of pregnancy loss (RR = 0.528, 95% CI: 0.344-0.812) and an increased risk of small-for-gestational-age infants (RR = 1.595, 95% CI: 1.023-2.485). Subgroup analyses suggested that the above effects of LT4 treatment were mainly from TPOAb-negative participants. LT4 treatment was associated with an increased risk of preterm birth (RR = 2.214, 95% CI: 1.016-4.825) in TPOAb-positive pregnant women with high-normal TSH levels. Conclusion: LT4 treatment was significantly associated with a lower risk of pregnancy loss and a higher risk of small-for-gestational-age infants in pregnant women with TSH levels of 2.5-10 mIU/L. An increased risk of preterm birth was observed in the LT4-treated group among TPOAb-positive participants with TSH levels of 2.5-4.0 mIU/L.
Keywords: levothyroxine; pregnancy outcomes; subclinical hypothyroidism; thyroid autoimmunity.