Assisted Reproductive Technology, Frozen Embryo Transfer (FET), Infertility, Intracytoplasmic Sperm Injection, In Vitro Fertilization (IVF), Subclinical Hypothyroidism
Conditions
Keywords
Levothyroxine, Subclinical Hypothyroidism, Infertility, Thyroid Disorders, IVF, ICSI, Frozen Embryo Transfer, FET, Assisted Reproductive Technology, Live Birth, Miscarriage, Pregnancy Outcomes, Thyroid Autoimmunity
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.
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.
Interventions
None listed
Sponsors
Mỹ Đức Hospital
Study design
Observational model
COHORT
Time perspective
RETROSPECTIVE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Live birth rate after the first frozen embryo transfer (FET) cycle | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical pregnancy rate | 6 weeks post-transfer | Ultrasonographic visualization of a gestational sac or embryo with cardiac activity. |
| Ongoing pregnancy rate | 12 weeks post-transfer | Presence of a fetus with heartbeat at ≥ 12 weeks' gestation. |
| Implantation rate | 3 weeks post-transfer | Number of gestational sacs divided by number of embryos transferred. |
| Miscarriage rate | Up to 22 weeks post-transfer | Spontaneous loss of a clinical pregnancy before 22 weeks' gestation. |
| Ectopic pregnancy rate | Up to 6 weeks post-transfer | Pregnancy outside the uterine cavity confirmed by ultrasound or surgery. |
| Multiple pregnancy rate | 6 weeks post-transfer | Detection of ≥2 gestational sacs on ultrasound. |
| Positive pregnancy test rate | 10-14 days post-transfer | Serum β-hCG ≥ 25 IU/mL after embryo transfer. |
| Gestational hypertension/preeclampsia | After 20 weeks' gestation | Gestational hypertension/preeclampsia is defined as the development of hypertension with or without proteinuria after 20 weeks of gestation. |
| Gestational diabetes mellitus | 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. |
| Neonatal birthweight | At delivery | Infant weight at delivery (low \<2500 g; very low \<1500 g; high \>4000 g). |
| Congenital anomalies | at delivery | Congenital anomalies are defined as structural or functional disorders that occur during intra-uterine life and can be identified prenatally at birth. |
| Neonatal death | Up to 1 month after delivery | Death of a live-born infant within 28 days of birth. |
| Preterm birth rate | At delivery | defined as a birth that takes place after 22 weeks and before 37 completed weeks of gestational age. |
Countries
Vietnam
Contacts
Primary ContactHoanh Kieu Tran, Doctor
Backup ContactLan Thi Ngoc Vuong, Assoc. Prof.
Outcome results
None listed