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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.
This study is a target trial specified (a randomized controlled trial between the Intervention (Exposed) Group and the Control (Unexposed) Group).
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
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| Measure | Description | Time Frame |
|---|---|---|
| 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) |
| Measure | Description | Time Frame |
|---|---|---|
| Positive pregnancy test rate | Serum β-hCG ≥ 25 IU/mL after embryo transfer. | 10-14 days post-transfer |
| Clinical pregnancy rate | Ultrasonographic visualization of a gestational sac or embryo with cardiac activity. |
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Inclusion Criteria:
Exclusion Criteria:
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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.
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| 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 |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| My Duc Hospital | Recruiting | Ho Chi Minh City | Ho Chi Minh | 700000 | Vietnam |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 12751777 | Background | 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. | |
| 28414788 | 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. |
| Label | URL |
|---|---|
| ClinicalTrials.gov registration (once approved) | View source |
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| 6 weeks post-transfer |
| Ongoing pregnancy rate | Presence of a fetus with heartbeat at ≥ 12 weeks' gestation. | 12 weeks post-transfer |
| Implantation rate | Number of gestational sacs divided by number of embryos transferred. | 3 weeks post-transfer |
| Miscarriage rate | Spontaneous loss of a clinical pregnancy before 22 weeks' gestation. | Up to 22 weeks post-transfer |
| Ectopic pregnancy rate | Pregnancy outside the uterine cavity confirmed by ultrasound or surgery. | Up to 6 weeks post-transfer |
| Multiple pregnancy rate | Detection of ≥2 gestational sacs on ultrasound. | 6 weeks post-transfer |
| Preterm birth rate | defined as a birth that takes place after 22 weeks and before 37 completed weeks of gestational age. | At delivery |
| Gestational hypertension/preeclampsia | 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 | 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 |
| Neonatal birthweight | Infant weight at delivery (low <2500 g; very low <1500 g; high >4000 g). | At delivery |
| Congenital anomalies | Congenital anomalies are defined as structural or functional disorders that occur during intra-uterine life and can be identified prenatally at birth. | at delivery |
| Neonatal death | Death of a live-born infant within 28 days of birth. | Up to 1 month after delivery |
| My Duc Hospital | Completed | Ho Chi Minh City | Ho Chi Minh | 700000 | Vietnam |
| 33639909 | 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. |
| 27112035 | 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. |
| 21193190 | 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. |
| University of Medicine and Pharmacy at Ho Chi Minh City - Reproductive Endocrinology Unit | View source |
| ID | Term |
|---|---|
| D007246 | Infertility |
| D013959 | Thyroid Diseases |
| D000022 | Abortion, Spontaneous |
| ID | Term |
|---|---|
| D000091662 | Genital Diseases |
| D000091642 | Urogenital Diseases |
| D004700 | Endocrine System Diseases |
| D011248 | Pregnancy Complications |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
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