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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
796
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.
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.
Sun Yat-Sen Memorial Hospital
Guangzhou, Guangdong, China
RECRUITINGSun Yat-Sen Memorial Hospital of Sun Yat-Sen University
Guangzhou, Guangdong, China
NOT_YET_RECRUITINGBirth of a living child beyond 28 weeks
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.
Time frame: After birth, within 24 months after randomization
Clinical pregnancy at 5 to 8 weeks
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.
Time frame: At 5-8 weeks of pregnancy
Miscarriage <28 weeks
Miscarriage that occurs less than 28 weeks of gestation
Time frame: At 28 weeks of pregnancy
Gestation at miscarriage, weeks
Gestation at miscarriage, weeks
Time frame: After the time of miscarriage, within 24 months after eligibility
On-going pregnancy at 12 weeks
On-going pregnancy at 12 weeks
Time frame: At 12 weeks of pregnancy
Gestation at delivery >34 weeks/>37 weeks
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.
Time frame: After birth, within 24 months after eligibility
Gestation at delivery, weeks
Gestation at delivery, weeks
Time frame: After birth, within 24 months after eligibility
Birth weight, grams
Birth weight, grams
Time frame: At birth, within 24 months after eligibility
APGAR score at 1 minute/5 minutes
APGAR score at 1 minute/5 minutes of the neonates.
Time frame: After birth, within 24 months after eligibility
birth defects
Birth defects of the neonates.
Time frame: At or short after birth, within 24 months after eligibility
Maternal antenatal complications,intrapartum complications,maternal postnatal complications
Hypertensive disorders of pregnancy, gestational diabetes, placenta previa, placental abruption, polyhydramnios, oligohydramnios, fetal growth restriction, postpartum hemorrhage and so on.
Time frame: up to birth/immediately after delivery
Time to 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).
Time frame: At 5-8 weeks of pregnancy
live birth rate after at least 28 weeks of gestation among pregnant patients
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.
Time frame: After birth, within 24 months after randomization
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