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

NCT07257250 | Recruiting

• 1 other identifier: 13/25/DD-BVMD
• Study Type: observational
• Target: 900
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

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

Keywords

Levothyroxine; Subclinical Hypothyroidism; Infertility; Thyroid Disorders; IVF; ICSI; Frozen Embryo Transfer; FET; Assisted Reproductive Technology; Live Birth; Miscarriage; Pregnancy Outcomes; Thyroid Autoimmunity

Outcome Measures

Primary Outcomes (1)

• 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.

  At delivery (within approximately 9 months after embryo transfer)

Secondary Outcomes (13)

• 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

Study Arms (2)

Levothyroxine-Treated Group

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

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.

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

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.

You may qualify if:

• 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).

You may not qualify if:

• 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).

Sponsors & Collaborators

• Mỹ Đức Hospital: lead

Study Sites (2)

My Duc Hospital

Ho Chi Minh City, Ho Chi Minh, 700000, Vietnam

RECRUITING

My Duc Hospital

Ho Chi Minh City, Ho Chi Minh, 700000, Vietnam

COMPLETED

Related Publications (5)

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

Related Links

• ClinicalTrials.gov registration (once approved)
• University of Medicine and Pharmacy at Ho Chi Minh City - Reproductive Endocrinology Unit

MeSH Terms

Conditions

Infertility; Thyroid Diseases; Abortion, Spontaneous

Condition Hierarchy (Ancestors)

Genital Diseases; Urogenital Diseases; Endocrine System Diseases; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications

Central Study Contacts

Hoanh Kieu Tran, Doctor

CONTACT

+84 982 741 425; trankieuhoanh@myduchospital.vn

Lan Thi Ngoc Vuong, Assoc. Prof.

CONTACT

+84 901 183 918; drlan@yahoo.com.vn

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 20, 2025
• First Posted: December 2, 2025
• Study Start: January 1, 2019
• Primary Completion: December 30, 2024
• Study Completion: March 30, 2026
• Last Updated: January 14, 2026

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

VN (2)