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

January 13, 2026 updated by: Mỹ Đức Hospital

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

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.

Study Overview

Status

Recruiting

Conditions

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.

Study Type

Observational

Enrollment (Estimated)

900

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

  • Name: Lan Thi Ngoc Vuong, Assoc. Prof.
  • Phone Number: +84 901 183 918
  • Email: drlan@yahoo.com.vn

Study Locations

  • Vietnam
    • Ho Chi Minh
      • Ho Chi Minh City, Ho Chi Minh, Vietnam, 700000
      • Ho Chi Minh City, Ho Chi Minh, Vietnam, 700000
        • Completed
        • My Duc Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult

Accepts Healthy Volunteers

No

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.

Description

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).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Live birth rate after the first frozen embryo transfer (FET) cycle
Time Frame: 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.
At delivery (within approximately 9 months after embryo transfer)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Positive pregnancy test rate
Time Frame: 10-14 days post-transfer
Serum β-hCG ≥ 25 IU/mL after embryo transfer.
10-14 days post-transfer
Clinical pregnancy rate
Time Frame: 6 weeks post-transfer
Ultrasonographic visualization of a gestational sac or embryo with cardiac activity.
6 weeks post-transfer
Ongoing pregnancy rate
Time Frame: 12 weeks post-transfer
Presence of a fetus with heartbeat at ≥ 12 weeks' gestation.
12 weeks post-transfer
Implantation rate
Time Frame: 3 weeks post-transfer
Number of gestational sacs divided by number of embryos transferred.
3 weeks post-transfer
Miscarriage rate
Time Frame: Up to 22 weeks post-transfer
Spontaneous loss of a clinical pregnancy before 22 weeks' gestation.
Up to 22 weeks post-transfer
Ectopic pregnancy rate
Time Frame: Up to 6 weeks post-transfer
Pregnancy outside the uterine cavity confirmed by ultrasound or surgery.
Up to 6 weeks post-transfer
Multiple pregnancy rate
Time Frame: 6 weeks post-transfer
Detection of ≥2 gestational sacs on ultrasound.
6 weeks post-transfer
Preterm birth rate
Time Frame: At delivery
defined as a birth that takes place after 22 weeks and before 37 completed weeks of gestational age.
At delivery
Neonatal birthweight
Time Frame: At delivery
Infant weight at delivery (low <2500 g; very low <1500 g; high >4000 g).
At delivery
Neonatal death
Time Frame: Up to 1 month after delivery
Death of a live-born infant within 28 days of birth.
Up to 1 month after delivery
Gestational hypertension/preeclampsia
Time Frame: After 20 weeks' gestation
Gestational hypertension/preeclampsia is defined as the development of hypertension with or without proteinuria after 20 weeks of gestation.
After 20 weeks' gestation
Gestational diabetes mellitus
Time Frame: 24-28 weeks' gestation
Gestational diabetes mellitus is diagnosed by 75-g Oral Glucose Tolerance Test (OGTT) with abnormal fasting or postload glucose at 24-28 weeks.
24-28 weeks' gestation
Congenital anomalies
Time Frame: at delivery
Congenital anomalies are defined as structural or functional disorders that occur during intra-uterine life and can be identified prenatally at birth.
at delivery

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Mỹ Đức Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 1, 2019

Primary Completion (Actual)

December 30, 2024

Study Completion (Estimated)

March 30, 2026

Study Registration Dates

First Submitted

November 20, 2025

First Submitted That Met QC Criteria

November 20, 2025

First Posted (Estimated)

December 2, 2025

Study Record Updates

Last Update Posted (Actual)

January 14, 2026

Last Update Submitted That Met QC Criteria

January 13, 2026

Last Verified

December 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 13/25/DD-BVMD

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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