Impact of Late-Follicular Phase Elevated Serum Progesterone on Cumulative Live Birth Rates: Is There a Deleterious Effect on Embryo Quality?

Multiple treatment attempts are generally required to achieve a live birth in women receiving assisted reproductive techniques. To provide patients with better prognostic information, increasing efforts have beenmade to report in vitro fertilization (IVF) success rates as cumulative live-birth rates (LBRs). Whether the supraphysiological increase in serumprogesterone during ovarian stimulation influences the success of assisted reproductive technique has been debated over the last 30 years. Some investigators suggest that there is no association between elevated progesterone (EP) levels and IVF pregnancy outcomes, whereas others believe that increased serum P levels adversely affect both embryo quality (EQ) and cumulative LBR. Evidence for a potential association between EP and EQ is lacking. The aim of this retrospective cohort study was to determine whether late follicular phase EP has a deleterious impact on EQ and cumulative LBRs. The study was conducted at a single center between 2010 and 2015. A retrospective analysis was performed of all gonadotropin-releasing hormone (GnRH) antagonist down-regulated intracytoplasmic sperm injection (ICSI) cycles followed by a fresh embryo transfer. Only patients undergoing ICSI who performed ovarian stimulation under GnRH antagonist suppression were included. Embryos were transferred on day 3 or day 5. A validated electrochemiluminescence immunoassay was used to assess serum P levels on the day of human chorionic gonadotropin administration. Patients were categorized into 3 groups on the day of ovulation triggering based on the following P levels: low (= 0.50 ng/mL), medium (0.51-1.49 ng/mL), and high (= 1.50 ng/mL). The primary outcome measures were embryo utilization rates (number of embryos transferred or cryopreserved) and cumulative LBRs (defined as the delivery of the first live birth after either the fresh or one of the subsequent frozen embryo transfers). A total of 3400 cycles were included in the analysis. Multivariable regression analysis was used to control for potential confounders. With increasing serum P values, there was a significant increase in female age and the number of oocytes retrieved. As P levels increased, utilization rates for day 3 embryos decreased linearly (72.3%, 63.0%, and 45.4%, respectively), whereas for day 5 embryos, only the EP group showed a significant decrease in utilization (48.8%, 47.8%, and 38.8%, respectively). Moreover, the EP group was associated with a decrease in both fresh and cumulative LBRs when compared with the medium P group. The study was limited by its retrospective nature and restriction to patients who performed ICSI in a GnRH antagonist protocol. These findings demonstrate that EP is associated with a decrease in both embryo utilization rate and cumulative LBRs. The data suggest that EP may also be associated with a decrease in cumulative pregnancy outcomes by increasing embryo wastage. Further studies are needed to evaluate the potential benefit of additionalmeasures (besides the freeze-all strategy) tominimize the consequences of EP such as lowering the stimulation dose or using a step-down approach.