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Recruiting NCT07257250

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

— Observational Subclinical Hypothyroidism Infertility Assisted Reproductive Technology In Vitro Fertilization (IVF)

For patients and families

In plain language

An automatic summary of structured registry data. It is an orientation aid, not a substitute for the official protocol or a physician assessment.

What is being studied
This is an observational study: the protocol does not assign a study treatment.
Who it may be relevant to
Registry conditions: Subclinical Hypothyroidism, Infertility, Assisted Reproductive Technology, In Vitro Fertilization (IVF). Basic parameters: 18 years — 45 years · Female.
What needs checking
Age, condition and sex are only basic indicators. Prior treatment, laboratory values and other mandatory requirements appear in the eligibility criteria below.
Where it takes place
Vietnam
Next step
Save the trial, show it to the treating physician, and confirm current recruitment with the study center. Costs, documents and travel →

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Official title

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

Overview

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.

Detailed 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.

Primary outcome measures

  • Live birth rate after the first frozen embryo transfer (FET) cycle [Time frame: At delivery (within approximately 9 months after embryo transfer)]
Secondary outcome measures (12)
  • Positive pregnancy test rate [Time frame: 10-14 days post-transfer]
  • Clinical pregnancy rate [Time frame: 6 weeks post-transfer]
  • Ongoing pregnancy rate [Time frame: 12 weeks post-transfer]
  • Implantation rate [Time frame: 3 weeks post-transfer]
  • Miscarriage rate [Time frame: Up to 22 weeks post-transfer]
  • Ectopic pregnancy rate [Time frame: Up to 6 weeks post-transfer]
  • Multiple pregnancy rate [Time frame: 6 weeks post-transfer]
  • Preterm birth rate [Time frame: At delivery]
  • Gestational hypertension/preeclampsia [Time frame: After 20 weeks' gestation]
  • Gestational diabetes mellitus [Time frame: 24-28 weeks' gestation]
  • Neonatal birthweight [Time frame: At delivery]
  • Congenital anomalies [Time frame: at delivery]

Eligibility criteria

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).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model
Cohort

Study locations

Vietnam · 2 centers
  • My Duc Hospital — Ho Chi Minh City
  • My Duc Hospital — Ho Chi Minh City

Publications

  • 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

Identifiers

NCT: NCT07257250 · 13/25/DD-BVMD

Primary sources (government registries)

View this study on ClinicalTrials.gov ↗