Effectiveness of Levothyroxine Treatment on In Vitro Fertilization and Pregnancy Outcome in Women With Subclinical Hypothyroidism and Infertility: A Target Trial Emulation
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 900
- 试验地点
- 3
- 主要终点
- Live birth rate after the first frozen embryo transfer (FET) cycle
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Retrospective
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •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).
排除标准
- •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).
结局指标
主要结局
Live birth rate after the first frozen embryo transfer (FET) cycle
时间窗: At delivery (within approximately 9 months after embryo transfer)
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.
次要结局
- Positive pregnancy test rate(10-14 days post-transfer)
- Clinical pregnancy rate(6 weeks post-transfer)
- Ongoing pregnancy rate(12 weeks post-transfer)
- Implantation rate(3 weeks post-transfer)
- Miscarriage rate(Up to 22 weeks post-transfer)
- Ectopic pregnancy rate(Up to 6 weeks post-transfer)
- Multiple pregnancy rate(6 weeks post-transfer)
- Preterm birth rate(At delivery)
- Gestational hypertension/preeclampsia(After 20 weeks' gestation)
- Gestational diabetes mellitus(24-28 weeks' gestation)
- Neonatal birthweight(At delivery)
- Congenital anomalies(at delivery)
- Neonatal death(Up to 1 month after delivery)