Effect of Metformin on Premature Luteinization and Pregnancy Outcomes in Intracytoplasmic Sperm Injection-Fresh Embryo Transfer Cycles: A Randomized Double-Blind Controlled Trial

Abstract

Background: Premature luteinization (PL) is not unusual in in vitro fertilization (IVF) and could not be whollyavoided by using either gonadotropin-releasing hormone (GnRH) agonists or GnRH antagonist regimens. The studyaims to evaluate metformin’s efficacy in preventing PL in fresh GnRH antagonist intracytoplasmic sperm injection(ICSI) cycles with cleavage-stage embryo transfer.Materials and Methods: This randomized, double-blind, placebo-controlled trial was conducted in a tertiary universityIVF center. We recruited infertile women who were scheduled to perform their first or second ICSI trial. Eligiblewomen were recruited and randomized in a 1:1 ratio into two groups. Metformin was administered in a dose of 1500mg per day since the start of contraceptive pills in the cycle antecedent to stimulation cycle until the day of ovulationtriggering, while women in the placebo group received a placebo for the same regimen and duration. The primaryoutcome was the incidence of PL, defined as serum progesterone (P) on the triggering day ≥1.5 ng/mL. Secondaryoutcomes comprised the live birth, ongoing pregnancy, implantation, and good-quality embryos rates.Results: The trial involved 320 eligible participants (n=160 in each group). Both groups had comparable stimulationdays, endometrial thickness, peak estradiol levels, number of oocytes retrieved, and number of mature oocytes. Metformingroup experienced lower level of serum P (p <0.001) and incidence of PL (10 vs. 23.6%, P=0.001). Moreover,lower progesterone/estradiol (P/E) ratio and progesterone to mature oocyte index (PMOI) (P=0.002 and P=0.002,respectively) were demonstrated in women receiving metformin. Metformin group generated a better rate of goodqualityembryos (P=0.005) and ongoing pregnancy (43.8 vs. 31.8%, P=0.026). A similar trend, though of borderlinesignificance, was observed in the live birth rate in favor of metformin administration (38.15 vs. 27.5%, P=0.04).Conclusion: Metformin could be used in patients with potential PL to improve fresh cycle outcomes by preventing PL(Registration number: NCT03088631).

Keywords

• infertility
• intracytoplasmic sperm injection
• metformin
• pregnancy outcomes