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

Официальное название

Effectiveness of Levothyroxine Treatment on In Vitro Fertilization and Pregnancy Outcome in Women With Subclinical Hypothyroidism and Infertility: A Target Trial Emulation

Обзор

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.

Подробное описание

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.

Первичные конечные точки

• Live birth rate after the first frozen embryo transfer (FET) cycle [Срок оценки: At delivery (within approximately 9 months after embryo transfer)]

Вторичные конечные точки (12)

• Positive pregnancy test rate [Срок оценки: 10-14 days post-transfer]
• Clinical pregnancy rate [Срок оценки: 6 weeks post-transfer]
• Ongoing pregnancy rate [Срок оценки: 12 weeks post-transfer]
• Implantation rate [Срок оценки: 3 weeks post-transfer]
• Miscarriage rate [Срок оценки: Up to 22 weeks post-transfer]
• Ectopic pregnancy rate [Срок оценки: Up to 6 weeks post-transfer]
• Multiple pregnancy rate [Срок оценки: 6 weeks post-transfer]
• Preterm birth rate [Срок оценки: At delivery]
• Gestational hypertension/preeclampsia [Срок оценки: After 20 weeks' gestation]
• Gestational diabetes mellitus [Срок оценки: 24-28 weeks' gestation]
• Neonatal birthweight [Срок оценки: At delivery]
• Congenital anomalies [Срок оценки: at delivery]

Критерии участия

Критерии включения

• 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).

Критерии исключения

• 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).

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

Вьетнам · 2 центра

• My Duc Hospital — Ho Chi Minh City
• My Duc Hospital — Ho Chi Minh City

Публикации

• Poppe K, Glinoer D. Thyroid autoimmunity and hypothyroidism before and during pregnancy. Hum Reprod Update. 2003 Mar-Apr;9(2):149-61. doi: 10.1093/humupd/dmg012. PMID 12751777
• Zhang Y, Wang H, Pan X, Teng W, Shan Z. Patients with subclinical hypothyroidism before 20 weeks of pregnancy have a higher risk of miscarriage: A systematic review and meta-analysis. PLoS One. 2017 Apr 17;12(4):e0175708. doi: 10.1371/journal.pone.0175708. eCollection 2017. PMID 28414788
• Bein M, Yu OHY, Grandi SM, Frati FYE, Kandil I, Filion KB. Levothyroxine and the risk of adverse pregnancy outcomes in women with subclinical hypothyroidism: a systematic review and meta-analysis. BMC Endocr Disord. 2021 Feb 27;21(1):34. doi: 10.1186/s12902-021-00699-5. PMID 33639909
• Maraka S, Singh Ospina NM, O'Keeffe DT, Rodriguez-Gutierrez R, Espinosa De Ycaza AE, Wi CI, Juhn YJ, Coddington CC 3rd, Montori VM, Stan MN. Effects of Levothyroxine Therapy on Pregnancy Outcomes in Women with Subclinical Hypothyroidism. Thyroid. 2016 Jul;26(7):980-6. doi: 10.1089/thy.2016.0014. Epub 2016 May 16. PMID 27112035
• Kim CH, Ahn JW, Kang SP, Kim SH, Chae HD, Kang BM. Effect of levothyroxine treatment on in vitro fertilization and pregnancy outcome in infertile women with subclinical hypothyroidism undergoing in vitro fertilization/intracytoplasmic sperm injection. Fertil Steril. 2011 Apr;95(5):1650-4. doi: 10.1016/j.fertnstert.2010.12.004. Epub 2010 Dec 30. PMID 21193190

Идентификаторы

NCT: NCT07257250 · 13/25/DD-BVMD

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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