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.
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).
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).
Infertile women aged 18-45 years diagnosed with subclinical hypothyroidism (TSH 4.2-\<10 mIU/L, normal FT4) who underwent IVF/ICSI with subsequent frozen embryo transfer (FET) at My Duc Hospital and My Duc Phu Nhuan Hospital, Ho Chi Minh City, Vietnam, between 2019 and 2024.
Cohort
Retrospective
Not listed
Live birth rate after the first frozen embryo transfer (FET) cycle
Delivery of a neonate showing any sign of life (heartbeat, umbilical cord pulsation, or movement) at ≥ 22 weeks' gestation after the nearest frozen embryo transfer cycle performed following levothyroxine treatment (or no treatment) in women with subclinical hypothyroidism undergoing IVF/ICSI.
Positive pregnancy test rate
Serum β-hCG ≥ 25 IU/mL after embryo transfer.
Clinical pregnancy rate
Ultrasonographic visualization of a gestational sac or embryo with cardiac activity.
Ongoing pregnancy rate
Presence of a fetus with heartbeat at ≥ 12 weeks' gestation.
Implantation rate
Number of gestational sacs divided by number of embryos transferred.
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