In-Vitro Fertilization, Metformin, Prediabetes
Conditions
Brief summary
To evaluate the efficacy and safety of metformin pretreatment on reproductive outcomes in infertile women with prediabetes.
Detailed description
To evaluate the efficacy and safety of metformin pretreatment on reproductive outcomes in infertile women with prediabetes and to determine whether either starting metformin pretreatment before ovarian stimulation (aiming at improving the quality of oocyte/embryo) or starting before frozen embryo transfer (FET) (aiming at improving the receptivity of endometrium) could increase the chance of a healthy live birth compared with placebo.
Interventions
DRUGMetformin pretreatment before ovarian stimulation
The enrolled patients will be prescribed metformin 850mg twice daily for at least 4 weeks prior to ovarian stimulation till oocyte retrieval.
DRUGPlacebo pretreatment before ovarian stimulation
The enrolled patients will be prescribed placebo 850mg twice daily for at least 4 weeks prior to ovarian stimulation till oocyte retrieval.
DRUGMetformin pretreatment before endometrial preparation for frozen embryo transfer
After oocyte retrieval, the enrolled patients will be prescribed metformin 850mg twice daily for at least 4 weeks before endometrial preparation for frozen embryo transfer and till the establishment of clinical pregnancy (7-8 weeks gestation) after the first frozen embryo transfer.
DRUGPlacebo pretreatment before endometrial preparation for frozen embryo transfer
After oocyte retrieval, the enrolled patients will be prescribed placebo 850mg twice daily for at least 4 weeks before endometrial preparation for frozen embryo transfer and till the establishment of clinical pregnancy (7-8 weeks gestation) after the first frozen embryo transfer.
Sponsors
Ren Ji Hospital of Shanghai Jiao Tong University
Women's Hospital of Zhejiang University
Shengjing Hospital
Nanjing Medical University
General Hospital of Ningxia Medical University
West China Second University Hospital
Maternal and Child Health Hospital of Henan Province
Qingdao women's and children's Hospital
Shandong University
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
20 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
1. Women who are diagnosed with prediabetes by ADA criteria, including either IFG, IGT, or HbA1C 5.7-6.4%. 2. Women aged 20-40 years. 3. Women who plan to undergo a new cycle of IVF, ICSI, or PGT-A.
Exclusion criteria
1. Women who are diagnosed with diabetes according to the ADA criteria11,12, which is meeting one of the following criteria: fasting plasma glucose ≥7.0mmol/L, 2-h plasma glucose during 75-g OGTT ≥11.1mmol/L, HbA1c≥6.5%, or a random plasma glucose≥11.1mmol/L. 2. Women who are taking medicine that interfere with glucose metabolism, such as metformin, oral anti-diabetic agents (sulfonylureas, glinides, thiazolidinediones, α-glycosidase inhibitors, GLP-1 receptor agonist, etc.), weight loss drugs (i.e.orlistat, etc.), glucocorticoids, and growth hormones within 2 months before enrollment. 3. Women with un-corrected hyperthyroidism or hypothyroidism. 4. Women with congenital or acquired abnormal uterine cavity including septate uterus, unicornous uterus, uterus duplex, and intrauterine adhesions. 5. Women with a diagnosis of adenomyosis. 6. Women with untreated hydrosalpinx. 7. Women who plan to undergo PGT-SR or PGT-M. 8. Women with major medical comorbidities, such as known liver disease, known renal disease, or known significant anemia.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| healthy live birth | From the date of randomization until delivery after the first embryo transfer, up to 16 months | defined as a singleton live birth at ≥37 weeks, with infant birth weight between 2500 and 4000g and without a major congenital anomaly. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in fasting glucose level | From the date of randomization until the establishment of clinical pregnancy after the first embryo transfer, up to 26 weeks | change in fasting glucose level from baseline to the establishment of clinical pregnancy. |
| Change in fasting insulin level | From the date of randomization until the establishment of clinical pregnancy after the first embryo transfer, up to 26 weeks | change in fasting insulin level from baseline to the establishment of clinical pregnancy. |
| Change in 2-h levels of glucose after 75-g OGTT | From the date of randomization until the establishment of clinical pregnancy after the first embryo transfer, up to 26 weeks | change in 2-h levels of glucose after 75-g OGTT from baseline to the establishment of clinical pregnancy. |
| Change in 2-h levels of insulin after 75-g OGTT | From the date of randomization until the establishment of clinical pregnancy after the first embryo transfer, up to 26 weeks | change in 2-h levels of insulin after 75-g OGTT from baseline to the establishment of clinical pregnancy. |
| Days of ovarian stimulation | From the date of randomization until the day of oocyte retrieved, up to 12 weeks | the duration of ovarian stimulation by exogenous gonadotropin |
| Total dose of gonadotropins | From the date of randomization until the day of oocyte retrieved, up to 12 weeks | the total dose of exogenous gonadotropin used during ovarian stimulation |
| Peak estradiol level | From the date of randomization until the day of oocyte retrieved, up to 12 weeks | the estradiol level on the day of hCG trigger |
| Number of oocyte retrieved | From the date of randomization until the day of oocyte retrieved, up to 12 weeks | the number of oocyte retrieved |
| Number of good-score embryos | From the date of randomization until the third day after oocyte retrieval, up to 12 weeks | the number of good-score embryos |
| Number of euploid embryos | From the date of randomization until the initiation of endometrial preparation for frozen embryo transfer, up to 20 weeks | the number of euploid embryos |
| OHSS | From the day of oocyte retrieved until the initiation of endometrial preparation for the first frozen embryo transfer, up to 8 weeks | ovarian hyperstimulation syndrome was defined according to the Golan criteria |
| Clinical pregnancy | 30-35 days after the first frozen embryo transfer | defined as the ultrasound confirmation of at least one intrauterine gestational sac |
| Change in BMI | From the date of randomization until the establishment of clinical pregnancy after the first embryo transfer, up to 26 weeks | change in body mass index (BMI) from baseline to the establishment of clinical pregnancy. |
| Pregnancy loss | From the date of confirmation of pregnancy until the date of pregnancy loss, up to 9 months | defined as pregnancies that eventuate in a spontaneous abortion or therapeutic abortion that occurred throughout pregnancy. |
| Live birth | From the date of randomization until delivery after the first embryo transfer, up to 16 months | defined as the delivery of any neonate with signs of life at ≥ 28 weeks of gestation |
| Incidences of obstetric and neonatal complications | From the establishment of clinically recognized pregnancy until six weeks after delivery after the first embryo transfer, up to 11 months | including gestational diabetes mellitus, pre-eclampsia, premature rupture of membrane, placenta previa, placental abruption, congenital anomalies, postpartum hemorrhage, stillbirth, neonatal respiratory distress syndrome, neonatal jaundice, neonatal infection, neonatal death. |
| Gestational weight gain | at delivery | maternal weight gain during pregnancy |
| Birth weight | at delivery | birth weight of the newborn at delivery |
| LGA | at delivery | defined as the birthweight above the 90th percentile for gestational age based on a sex-specific reference |
| SGA | at delivery | defined as the birthweight below the 10th percentile for gestational age based on a sex-specific reference |
| LBW | at delivery | the infant born weighing less than 2500g |
| Macrosomia | at delivery | the infant born weighing larger than 4000g |
| Adverse events | From the date of randomization until six weeks after delivery after the first embryo transfer, up to 18 months | adverse event (AE) and serious adverse event (SAE) |
| Cumulative live birth | From the date of randomization until delivery, up to 28 months | define as women achieving live birth after all the cycles of embryo transfer per oocyte retrieval that performed within one year after randomization. |
| Singleton or twin pregnancy | 30-35 days after the first frozen embryo transfer | the number of intrauterine gestational sacs |
Countries
China
Contacts
Primary ContactZi-Jiang Chen, Professor
Outcome results
None listed