Levothyroxine Treatment and IVF Outcomes in Women With Subclinical Hypothyroidism: A Target Trial Emulation (LESI)

Mỹ Đức Hospital

Status: Enrolling

Conditions: In Vitro Fertilization (IVF); Infertility; Frozen Embryo Transfer (FET); Assisted Reproductive Technology; Intracytoplasmic Sperm Injection; Subclinical Hypothyroidism

Study type: Observational

Funder types: Other

Identifiers

NCT07257250

13/25/DD-BVMD

Details and patient eligibility

About

Subclinical hypothyroidism (SCH) is defined by elevated thyroid-stimulating hormone (TSH) with normal free thyroxine (fT4) levels. It affects approximately 5-7% of women of reproductive age and may negatively influence outcomes of assisted reproductive technology (ART). During controlled ovarian stimulation, rising estradiol increases thyroxine-binding globulin and thyroid hormone requirements. These physiological changes, combined with increased metabolic demand in early pregnancy, may worsen SCH and contribute to adverse outcomes such as miscarriage, preterm birth, and hypertensive disorders of pregnancy.

Although levothyroxine (LT4) is routinely used to treat overt hypothyroidism, evidence for its benefit in SCH, especially among infertile women undergoing In Vitro Fertilization (IVF) or Intra-Cytoplasmic Sperm Injection (ICSI) with frozen embryo transfer (FET), remains inconclusive. Some trials and meta-analyses have shown reductions in miscarriage and neonatal mortality, while others have found no improvement in ART or obstetric outcomes.

This study aims to evaluate the effectiveness of levothyroxine therapy on IVF/FET outcomes and subsequent pregnancy results in women with subclinical hypothyroidism and infertility. This retrospective cohort study will emulate the target trial to evaluate whether LT4 treatment, titrated to achieve a pre-transfer TSH < 2.5 mIU/L, improves implantation, live birth, and obstetric outcomes compared with expectant management.

Full description

This study is a target trial specified (a randomized controlled trial between the Intervention (Exposed) Group and the Control (Unexposed) Group).

• Intervention (Exposed) Group: Women treated with levothyroxine 25-50 µg/day initiated before the planned FET, titrated every 2-4 weeks to achieve TSH < 2.5 mIU/L before transfer.
• Control (Unexposed) Group: Women managed expectantly without thyroid medication (Before 2020, LT4 use was at the discretion of clinicians; since 2020, the Reproductive Endocrinology Unit has standardized treatment for most SCH patients)

The target trial is emulated using observational data of infertile women aged 18-45 years diagnosed with subclinical hypothyroidism, defined as TSH 4.2-<10 mIU/L and FT4 0.92-1.68 ng/dL, undergoing IVF/ICSI followed by FET in My Duc Hospital and My Duc Phu Nhuan Hospital (Ho Chi Minh City, Vietnam), using routinely collected medical records from January 1, 2019, to December 31, 2024.

Enrollment: 900 estimated patients

Sex: Female

Ages: 18 to 45 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Women aged 18-45 years.
• Diagnosed with subclinical hypothyroidism (TSH 4.2-<10 mIU/L with FT4 0.92-1.68 ng/dL).
• Undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) followed by frozen embryo transfer (FET).

Exclusion criteria

• Overt hypothyroidism (TSH ≥10 mIU/L and FT4 ≤0.92 ng/dL).
• Current or recent (within 1 month) use of drugs affecting thyroid function (levothyroxine, amiodarone, methimazole, propylthiouracil).

Trial design

900 participants in 2 patient groups

Levothyroxine-Treated Group

Description:

Women with subclinical hypothyroidism (TSH 4.2-\<10 mIU/L, normal FT4) treated with levothyroxine 25-50 µg/day before frozen embryo transfer (FET). The dose was adjusted every 2-4 weeks to achieve a pre-transfer TSH \<2.5 mIU/L. Outcomes including implantation, pregnancy, and live birth rates were assessed after the nearest post-treatment FET cycle.

Non-Treated (Control) Group

Description:

Women with subclinical hypothyroidism (TSH 4.2-\<10 mIU/L, normal FT4) who did not receive levothyroxine treatment prior to frozen embryo transfer. Participants were managed expectantly according to clinical judgment. Outcomes were compared with those of the treated group for IVF/ICSI-FET success and pregnancy results.