Effect of Metformin on Healthy Live Birth in Women With Prediabetes

Official title

Effect of Metformin on Healthy Live Birth After In-vitro Fertilization in Women With Prediabetes Mellitus: a Multicenter Double-blind Placebo Controlled Randomized Trial

Overview

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

• Drug Metformin 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.
• Drug Placebo 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.
• Drug Metformin 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.
• Drug Placebo 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.

Primary outcome measures

• healthy live birth [Time frame: From the date of randomization until delivery after the first embryo transfer, up to 16 months]

Secondary outcome measures (12)

• Change in BMI [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: From the date of randomization until the establishment of clinical pregnancy after the first embryo transfer, up to 26 weeks]
• Days of ovarian stimulation [Time frame: From the date of randomization until the day of oocyte retrieved, up to 12 weeks]
• Total dose of gonadotropins [Time frame: From the date of randomization until the day of oocyte retrieved, up to 12 weeks]
• Peak estradiol level [Time frame: From the date of randomization until the day of oocyte retrieved, up to 12 weeks]
• Number of oocyte retrieved [Time frame: From the date of randomization until the day of oocyte retrieved, up to 12 weeks]
• Number of good-score embryos [Time frame: From the date of randomization until the third day after oocyte retrieval, up to 12 weeks]
• Number of euploid embryos [Time frame: From the date of randomization until the initiation of endometrial preparation for frozen embryo transfer, up to 20 weeks]
• OHSS [Time frame: From the day of oocyte retrieved until the initiation of endometrial preparation for the first frozen embryo transfer, up to 8 weeks]

Eligibility criteria

Inclusion criteria

• Women who are diagnosed with prediabetes by ADA criteria, including either IFG, IGT, or HbA1C 5.7-6.4%.
• Women aged 20-40 years.
• Women who plan to undergo a new cycle of IVF, ICSI, or PGT-A.

Exclusion criteria

• 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.
• 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.
• Women with un-corrected hyperthyroidism or hypothyroidism.
• Women with congenital or acquired abnormal uterine cavity including septate uterus, unicornous uterus, uterus duplex, and intrauterine adhesions.
• Women with a diagnosis of adenomyosis.
• Women with untreated hydrosalpinx.
• Women who plan to undergo PGT-SR or PGT-M.
• Women with major medical comorbidities, such as known liver disease, known renal disease, or known significant anemia.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Factorial

Masking

Triple blind

Primary purpose

Treatment

Study locations

China · 1 center

• Shandong University — Jinan

Publications

• Wei Y, Xu Q, Yang H, Yang Y, Wang L, Chen H, Anderson C, Liu X, Song G, Li Q, Wang Q, Shen H, Zhang Y, Yan D, Peng Z, He Y, Wang Y, Zhang Y, Zhang H, Ma X. Preconception diabetes mellitus and adverse pregnancy outcomes in over 6.4 million women: A population-based cohort study in China. PLoS Med. 2019 Oct 1;16(10):e1002926. doi: 10.1371/journal.pmed.1002926. eCollection 2019 Oct. PMID 31574092
• Macintosh MC, Fleming KM, Bailey JA, Doyle P, Modder J, Acolet D, Golightly S, Miller A. Perinatal mortality and congenital anomalies in babies of women with type 1 or type 2 diabetes in England, Wales, and Northern Ireland: population based study. BMJ. 2006 Jul 22;333(7560):177. doi: 10.1136/bmj.38856.692986.AE. Epub 2006 Jun 16. PMID 16782722
• Egan AM, Dow ML, Vella A. A Review of the Pathophysiology and Management of Diabetes in Pregnancy. Mayo Clin Proc. 2020 Dec;95(12):2734-2746. doi: 10.1016/j.mayocp.2020.02.019. Epub 2020 Jul 28. PMID 32736942
• Bianco ME, Josefson JL. Hyperglycemia During Pregnancy and Long-Term Offspring Outcomes. Curr Diab Rep. 2019 Nov 21;19(12):143. doi: 10.1007/s11892-019-1267-6. PMID 31754898
• Farrar D, Simmonds M, Bryant M, Sheldon TA, Tuffnell D, Golder S, Dunne F, Lawlor DA. Hyperglycaemia and risk of adverse perinatal outcomes: systematic review and meta-analysis. BMJ. 2016 Sep 13;354:i4694. doi: 10.1136/bmj.i4694. PMID 27624087
• HAPO Study Cooperative Research Group; Metzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, Coustan DR, Hadden DR, McCance DR, Hod M, McIntyre HD, Oats JJ, Persson B, Rogers MS, Sacks DA. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med. 2008 May 8;358(19):1991-2002. doi: 10.1056/NEJMoa0707943. PMID 18463375
• Armengaud JB, Ma RCW, Siddeek B, Visser GHA, Simeoni U. Offspring of mothers with hyperglycaemia in pregnancy: The short term and long-term impact. What is new? Diabetes Res Clin Pract. 2018 Nov;145:155-166. doi: 10.1016/j.diabres.2018.07.039. Epub 2018 Aug 6. PMID 30092235
• Kitzmiller JL, Buchanan TA, Kjos S, Combs CA, Ratner RE. Pre-conception care of diabetes, congenital malformations, and spontaneous abortions. Diabetes Care. 1996 May;19(5):514-41. doi: 10.2337/diacare.19.5.514. No abstract available. PMID 8732721

Identifiers

NCT: NCT06064669 · MELT-PreDM

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗