Highlights
An umbrella review of 11 meta-analyses demonstrates that levothyroxine (LT4) supplementation significantly mitigates the risk of pregnancy loss, preterm delivery, and gestational hypertension.
The clinical benefit of LT4 is most pronounced when treatment is initiated in early pregnancy and among women with TSH levels greater than 4.0 mU/l.
While LT4 improves several key outcomes, it does not show a statistically significant impact on live birth rates, placental abruption, or the incidence of gestational diabetes.
Evidence quality varies, highlighting the need for precision medicine approaches to avoid overtreatment in low-risk populations.
Background: The Burden of Thyroid Dysfunction in Pregnancy
Thyroid hormones are essential for the maintenance of a healthy pregnancy and optimal fetal neurodevelopment, particularly in the first trimester before the fetal thyroid gland becomes functional. Subclinical hypothyroidism (SCH)—defined by elevated thyroid-stimulating hormone (TSH) levels with normal free thyroxine (FT4)—and the presence of thyroid peroxidase antibodies (TPOAb) are common clinical findings in reproductive-aged women. These conditions have long been associated with an increased risk of adverse obstetric outcomes, including miscarriage and preterm birth.
Despite numerous randomized controlled trials (RCTs) and meta-analyses, clinical guidelines have historically fluctuated regarding the universal application of levothyroxine (LT4) in these populations. The primary clinical challenge lies in identifying which patients derive tangible benefits from supplementation versus those who may be subjected to unnecessary medicalization. This umbrella review aims to synthesize existing high-level evidence to provide a definitive assessment of LT4’s efficacy across a spectrum of pregnancy outcomes.
Study Design and Methodology
This study utilized an umbrella review framework, which is designed to provide a high-level synthesis of systematic reviews and meta-analyses. The researchers conducted a comprehensive search of major databases, including PubMed, Embase, Web of Science, and the Cochrane Database of Systematic Reviews, through March 20, 2025.
Inclusion Criteria and Quality Assessment
The review focused on meta-analyses of RCTs assessing LT4 effects in women with SCH or TPOAb positivity. A total of 24 associations across six pregnancy outcomes were analyzed: pregnancy loss, preterm delivery, live birth, placental abruption, gestational hypertension, and gestational diabetes. The methodological quality of the included meta-analyses was rigorously evaluated using the AMSTAR 1 tool, while the quality of evidence for each outcome was graded using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) system. Of the 24 associations examined, 22 were rated as having high confidence according to AMSTAR 1 criteria.
Key Findings: Maternal and Fetal Outcomes
The umbrella review included 11 meta-analyses, providing a robust dataset for clinical interpretation. The results were categorized by outcome and the strength of evidence supporting the association.
Significant Reductions in Adverse Outcomes
The most compelling findings involved the reduction of pregnancy loss and preterm delivery. High-quality evidence (Class III) indicated that LT4 treatment reduced the risk of pregnancy loss by 57% (RR = 0.43) and preterm delivery by 44% (RR = 0.56). Furthermore, the risk of gestational hypertension was reduced by 37% (RR = 0.63), though this was supported by Class IV evidence.
Outcomes Showing No Significant Change
Interestingly, the review found that LT4 supplementation did not significantly alter the rates of live births, placental abruption, or gestational diabetes. These findings were supported by moderate-to-low-quality evidence. The lack of impact on live birth rates, despite the reduction in pregnancy loss, suggests a need for further investigation into the complexities of late-term pregnancy success and the multifactorial nature of live birth outcomes.
Clinical Nuances: The Importance of Timing and Thresholds
Sensitivity analyses revealed critical factors that determine the efficacy of LT4 therapy. These nuances are vital for clinicians when developing individualized treatment plans.
The Critical Window of Early Pregnancy
The reduction in pregnancy loss and preterm labor was significantly more pronounced when LT4 treatment was initiated during early pregnancy. Specifically, for pregnancy loss, early initiation resulted in a Relative Risk (RR) of 0.60 (P = 0.03). For preterm labor, the reduction was even more striking (RR = 0.58, P < 0.0001). This reinforces the importance of early screening and prompt intervention following the confirmation of pregnancy in women with known thyroid dysfunction.
TSH Thresholds for Treatment
The study highlighted a clear stratification of benefit based on TSH levels. Women with TSH levels exceeding 4.0 mU/l derived significantly greater benefits from LT4 treatment compared to those with TSH levels in the 2.5 to 4.0 mU/l range. This finding supports a more targeted approach, suggesting that aggressive treatment may be less necessary for women with mild TSH elevations unless other risk factors, such as TPOAb positivity, are present.
Expert Commentary and Clinical Implications
The findings of this umbrella review serve to refine current clinical practice. By integrating high-quality evidence, the study confirms that LT4 is a potent intervention for specific subsets of the pregnant population. However, it also serves as a warning against the risk of overtreatment.
Biological Plausibility
The mechanistic rationale for LT4 efficacy likely stems from its role in stabilizing the intrauterine environment. Adequate thyroid hormone levels are necessary for proper placentation and the suppression of inflammatory pathways that could otherwise trigger preterm labor or hypertensive disorders. In TPOAb-positive women, LT4 may help compensate for the limited thyroidal reserve caused by autoimmune-mediated damage.
Limitations and Cautions
While the umbrella review provides a high level of evidence, clinicians should remain mindful of certain limitations. Many of the component meta-analyses included studies with small sample sizes and potential selection biases. Additionally, the restriction of the search to English and Chinese language studies may limit the generalizability of the findings to all global populations. The heterogeneity in treatment methods and timing across trials also suggests that while the overall trend is positive, the “optimal” dose and protocol remain areas for further research.
Conclusion: Toward Precision Intervention
This umbrella review provides an evidence-based foundation for precision intervention in gestational thyroid disorders. LT4 supplementation is clearly beneficial for reducing pregnancy loss and preterm delivery, particularly in women with TSH > 4.0 mU/l or those with TPOAb positivity when treated early in gestation. Future research should prioritize standardized, large-scale studies to clarify dose-response thresholds and evaluate the long-term neurodevelopmental outcomes of children born to mothers receiving LT4. Until then, clinicians should adopt a risk-stratified management approach, balancing the clear benefits of intervention against the potential for over-medicalization in low-risk patients.
Funding and Registration
This work was supported by the National Key R&D Program of China (Grant No. 2023YFC2508300, 2023YFC2508303, and 2023YFC2508305), the National Science and Technology Major Project (Grant No. 2024ZD0533403), and the National Natural Science Foundation of China (Grant No. 82100831, 81570709, and 82470826). The study is registered with PROSPERO under the number CRD42024586105.
References
Wang J, Li J, Zhang J, Liu A, Yang W, Zhai X, Teng W, Li Y, Shan Z. Levothyroxine supplementation and pregnancy outcomes in women with thyroid disorders: an umbrella review of systematic reviews and meta-analyses of randomized controlled trials. Hum Reprod Open. 2025 Sep 8;2025(3):hoaf036. doi: 10.1093/hropen/hoaf036. PMID: 40978523.
