Hypothyroidism is a major problem which affects 0.3 to 12% of the global population ¹ and contributes significantly to morbidity. ² Broadly, it includes overt, central, and subclinical hypothyroidism, depending on the varied combinations of thyroid function test (TFT) markers. “Subclinical hypothyroidism (SCH)” is identified when “serum-free thyroxine (FT4)” and “free triiodothyronine (FT3)” levels are normal, but “thyroid-stimulating hormone (TSH)” levels are elevated. ³ The characteristic laboratory finding of subclinical hypothyroidism is an increased TSH level along with a normal T4 level. ⁴ While it is typically regarded as an asymptomatic condition, some patients may exhibit non-specific symptoms that could indicate hypothyroidism. The prevalence of SCH in the general population is notably high (4% to 20%) and varies by sex and age. It is more common in individuals over 60 years of age, with a prevalence of approximately 15% in women and 8% in men. ⁵ Of individuals with grade 1 subclinical hypothyroidism, 60% experienced a return of thyrotropin to normal levels within a five-year period. The yearly likelihood of advancing to overt hypothyroidism in these patients ranges from 2% to 4%, and is influenced by the presence of TPO antibodies. Among older adults (aged 65 and above), 46% of those with “grade 1 subclinical hypothyroidism” (TSH levels ranging from 4.5 to 6.9 mU/L) saw their thyrotropin normalize within two years, in contrast to only 7% of those with grade 2 subclinical hypothyroidism. ⁶ SCH in pregnancy significantly progresses to overt hypothyroidism in the post-pregnancy period (within 5 years). ⁷ In pregnant women, SCH has been reported to be associated with multiple “adverse pregnancy outcomes (APOs),” such as preeclampsia and preterm birth, among others. ^{8, 9} Higher risk for pregnancy loss, hypertensive disorders of pregnancy and placental abruption in SCH group has also been reported in the past meta-analyses. ^{10, 11}

While the therapeutic decision for overt hypothyroidism is fairly straightforward, treatment of SCH, especially the timing of the initiation of therapy, has been a point of discussion. In pregnant women, levothyroxine (LT4) treatment has been shown to reduce APOs, such as preterm birth, gestational hypertension, pregnancy loss, and neonatal mortality. ^{12– 14} Effect of LT4 therapy in specific sub-groups such as recurrent pregnancy loss is a gap to be explored in evidence synthesis. ¹⁵ Although multiple meta-analyses have reported the efficacy of LT4 therapy on pregnancy outcomes, ¹⁶ relatively long-term outcomes such as neurodevelopment in infancy have not been reported. For adult SCH patients, levothyroxine treatment has been recommended since low-quality evidence was present for the critical outcomes (as of 2019). ¹⁷ Peng In their systematic review of studies conducted until April 2020, Peng et al. reported a differential pattern of LT4 association with mortality among older and younger adults. ¹⁸ Treatment for SCH also needs to factor in the TPOAb positive and levels of TSH at diagnosis, since these factors have been shown to increase the risk of progression of SCH to overt hypothyroidism. ^{9, 19} An updated pooled systematic review on the effect of LT4 among the adults (non-pregnant women, young adults and old adults) is not available. In addition, important effect modifiers such as age, sex, comorbidity, initial TSH levels of patients (as reported by the studies), symptom status, and the type of control group used (placebo/no treatment/watchful waiting/delayed initiation) need to be explored to ascertain any differential effects of LT4 therapy among patients with SCH.

Considering the current burden of SCH surpassing overt hypothyroidism, and that this hidden thyroid dysfunction can lead to complications, reduced quality of life, productivity, and lack of a comprehensive systematic review assessing the impact of LT4 therapy in SCH including all population groups, the current “systematic review and meta-analysis (SRMA)” is being proposed. The objective of this systematic review is to assess the effect of LT4 therapy on the prevention of complications, adverse events, and quality of life among SCH patients.

The SRMA protocol adhered to the “Preferred Reporting Items for Systematic reviews and Meta-Analyses Protocols (PRISMA-P 2015)” guidelines (Extended Data: Table S1). The review is registered in the PROSPERO database (CRD420251270021).

The decision to initiate hormone replacement therapy for SCH has been controversial, with varied evidence profiles in different population groups. For pregnant women, it has been recommended to initiate LT4 therapy in cases of SCH, ¹⁹ whereas recommendations for adult SCH patients are against LT4 therapy. ¹⁷ However, even within pregnancy outcomes, systematic reviews have reported differential pooled estimates, with favorable (reduced APOs), ¹⁴ and neutral (no change in APOs), ²⁶ findings for LT4 therapy in SCH. The impact of co-morbidities on the effect of LT4 in SCH patients and specific outcomes, such as cardiovascular events, has been studied by certain primary studies. ^{27, 28} Studies have also assessed age group specific impact of the LT4 therapy in SCH outcomes, as well. ^{28, 29} Effect of the LT4 therapy in SCH infertile women on their fertility outcomes has also been reported in the past. ³⁰

The lack of certainty assessment (e.g., GRADE profile) in the outcomes reported is a lacuna in the existing systematic reviews on this topic, ^{14, 15, 18, 31} which seriously limits the transferability for guideline development. Through the current systematic review, we intend to provide a comprehensive, updated (until December 2025) evidence profile on the effect of LT4 therapy on important and critical patient outcomes (progression to overt hypothyroidism, mortality, complications, quality of life, acceptability, and costs) for multiple population groups (adults, non-pregnant women, infertile women, pregnant women, neonates, children, and co-morbidities). Subgroup analysis was planned in this review to explore the effect modification potential of all critical factors (age, TSH range for SCH diagnosis, symptom status, autoimmunity, and type of control group) on the direction and magnitude of the association between LT4 treatment and outcomes in SCH patients. GRADE profiling of critical and important outcomes will be performed in the index systematic review, which can provide certainty in the evidence pooled in the review.

Overall, the findings of the systematic review can inform the framing of the clinical guidelines for SCH management for all population groups, with or without conditional recommendations, as per the variations that may arise due to the subgroup analysis. The review can also reveal the differential effects, if any, according to the severity of the SCH (TSH levels and symptom status), which can enable layered recommendations instead of a blanket recommendation. The outputs from the SRMA can ensure robust guidelines centered on systematically collated, transparent, and critically appraised evidence, which in turn can enhance clinical practice and patient outcomes.

The SRMA also intends to bring out gaps in the existing literature (in terms of lack of adequate evidence in specific populations, specific outcomes, sub-groups, and quality of the studies conducted thus far). This can enable the formulation of research questions for future studies on the management of SCH using LT4 to address these gaps.

Not applicable, since it is systematic review of published articles.

The authors declare that they have not used AI tools in the creation of this article.