Euthyroid With Thyroid Antibodies, Recurrent Pregnancy Loss
Conditions
Keywords
live birth, euthyroid, thyroid peroxidase antibody, recurrent pregnancy loss
Brief summary
The goal of this clinical trial is to learn if combined treatment of levothyroxine and hydroxychloroquine would improve the live birth of euthyroid women with thyroid peroxidase antibodies and unexplained recurrent pregnancy loss. Researchers will compare combined treatment of levothyroxine and hydroxychloroquine to a treatment of levothyroxine alone to see if combined treatment works to improve live birth of euthyroid participants with thyroid peroxidase antibodies and unexplained recurrent pregnancy loss. Participants will: * Receive combined treatment of levothyroxine and hydroxychloroquine or treatment of levothyroxine alone every day at least 8 weeks before pregnancy, and continue their treatment till the end of pregnancy. * Visit the clinic 4 weeks and 8 weeks after their treatments, and every 12 weeks before they get pregnant for checkups and tests. During their pregnancy, they will visit the clinic before gestation of 12 weeks, and will be followed up with phone call in the second trimester and after parturition.
Detailed description
Thyroid peroxidase antibodies (TPO-Ab) in euthyroid women are associated with recurrent pregnancy loss. According to 2017 Guidelines of the American Thyroid Association, administration of levothyroxine (LT4) to TPO-Ab-positive euthyroid pregnant women with a prior history of loss may be considered given its potential benefits in comparison with its minimal risk. However, it is a weak recommendation with low-quality evidence. Recently published randomised clinical trials showed that administration of LT4 does not improve pregnancy outcomes of euthyroid thyroid peroxidase antibody positive women with recurrent pregnancy loss. Published data showed TPO-Ab is related to immune imbalance. Hydroxychloroquine is a widely used immune modulator even in fields of autoimmune disorders during pregnancy and lactation. Nevertheless, the effect of hydroxychloroquine combined with LT4 on live birth rate of euthyroid women with TPO-Ab and unexplained recurrent pregnancy loss is unclear. Therefore, we designed a multicenter RCT to verify the study hypothesis that combined treatment of levothyroxine and hydroxychloroquine would improve the live birth rate of euthyroid women with thyroid peroxidase antibodies and unexplained recurrent pregnancy loss.
Interventions
DRUGhydroxychloroquine and levothyroxine
Hydroxychloroquine sulfate tablets (Fenle, 0.1g) will be given at a total daily dose of 0.2g to 0.4g based on individual weight as described above. During the study, if TSH is higher than 4.0 mIU/L or exceeds the lower limit of the reference range of the center in the first trimester, or TSH level exceeds the normal range of the center during the second or the third trimester, subjects will be instructed to suspend the medication and visit the Department of Endocrinology.
DRUGLevothyroxine
Levothyroxine sodium tablets (Euthyrox, 50 μg) will be given 12.5μg \ 50 μg daily based on patients' TSH levels and weights as described above. During the study, if TSH is higher than 4.0 mIU/L or exceeds the lower limit of the reference range of the center in the first trimester, or TSH level exceeds the normal range of the center during the second or the third trimester, subjects will be instructed to suspend the medication and visit the Department of Endocrinology.
Sponsors
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
open-labeled multicenter randomized clinical trial
Eligibility
Sex/Gender
FEMALE
Age
20 Years to 40 Years
Healthy volunteers
No
Inclusion criteria
1. Women with history of two or more pregnancy loss with the same male partner (including biochemical pregnancies). 2. Karyotype analyses show no pathological abnormalities in each individual of the recruited couple. 3. Women aged between 20 and 40 years old (including 20 and 40). 4. Lupus anticoagulant (LA), anticardiolipin antibody (ACA), and anti-beta2-glycoprotein I antibodies (anti-β2-GP1 Ab) tests are all negative. 5. It is confirmed by ultrasound or hysteroscopy that there are no pathological lesions that affect the morphology of the uterine cavity (such as submucosal uterine fibroids, uterine malformations). 6. TPO-Ab positive (TPO-Ab \> 60 IU/mL using the Siemens kit of electrochemiluminescence method, or TPO-Ab \> 34 IU/mL using the Roche kit of chemiluminescence method). 7. Biochemically euthyroid. TSH, free triiodothyronine (FT3), and free thyroxine (T4) are all within the reference range of corresponding laboratory testing in each research center.
Exclusion criteria
1. Rheumatic diseases, such as systemic lupus erythematosus, undifferentiated connective tissue disease, etc. 2. Metabolic or endocrine diseases, such as diabetes. 3. Abnormal renal function: plasma creatinine level ≥130 μmol/L or abnormal liver function: alanine aminotransferase ≥80U/L or aspartate aminotransferase ≥80U/L. 4. Hypertension and malignant tumors. 5. Under treatment with glucocorticoids or immunosuppressor, including cyclosporine, azathioprine, prednisone, and methylprednisolone. 6. Body Mass Index (BMI) \>28kg/m2. 7. Past history of hyperthyroidism, hypothyroidism, and thyroid malignant tumors; 8. Allergy to 4-aminoquinoline compound, or those with retinal or visual field lesions caused by 4-aminoquinoline compound.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Birth of a living child beyond 28 weeks | After birth, within 24 months after randomization | The primary outcome is the proportion of women with a live birth at or beyond 28 completed weeks. This proportion will be calculated with the denominator totalling all women randomised, and the numerator (i.e., treatment successes) totalling women who conceive within 60 weeks of randomisation and go on to give live birth at or beyond 28 weeks gestation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Miscarriage <28 weeks | At 28 weeks of pregnancy | Miscarriage that occurs less than 28 weeks of gestation |
| Gestation at miscarriage, weeks | After the time of miscarriage, within 24 months after eligibility | Gestation at miscarriage, weeks |
| On-going pregnancy at 12 weeks | At 12 weeks of pregnancy | On-going pregnancy at 12 weeks |
| Gestation at delivery >34 weeks/>37 weeks | After birth, within 24 months after eligibility | Number of women who have a delivery at least 34 weeks of gestation. Number of women who have a delivery at least 37 weeks of gestation. |
| Gestation at delivery, weeks | After birth, within 24 months after eligibility | Gestation at delivery, weeks |
| Clinical pregnancy at 5 to 8 weeks | At 5-8 weeks of pregnancy | It is the proportion of women with a cardiac activity confirmed by ultrasound during 5 to 8 weeks of gestation. This proportion will be calculated with the denominator totalling all women randomised, and the numerator totalling women who have clinical pregnancy within 60 weeks of randomisation. |
| APGAR score at 1 minute/5 minutes | After birth, within 24 months after eligibility | APGAR score at 1 minute/5 minutes of the neonates. |
| birth defects | At or short after birth, within 24 months after eligibility | Birth defects of the neonates. |
| Maternal antenatal complications,intrapartum complications,maternal postnatal complications | up to birth/immediately after delivery | Hypertensive disorders of pregnancy, gestational diabetes, placenta previa, placental abruption, polyhydramnios, oligohydramnios, fetal growth restriction, postpartum hemorrhage and so on. |
| Time to pregnancy. | At 5-8 weeks of pregnancy | It refers to the time interval from patients trying to prepare for pregnancy (after 8 weeks of medication) to successful pregnancy (intrauterine pregnancy confirmed by ultrasound). |
| live birth rate after at least 28 weeks of gestation among pregnant patients | After birth, within 24 months after randomization | It is the proportion of women with a live birth at or beyond 28 of completed weeks. This proportion will be calculated with the denominator totalling all women who have clinical pregnancy within 60 weeks of randomisation, and the numerator totalling women who have a live birth at or beyond 28 of completed weeks. |
| Birth weight, grams | At birth, within 24 months after eligibility | Birth weight, grams |
Countries
China
Outcome results
None listed