Both high and low HCG day progesterone concentrations negatively affect live birth rates in IVF/ICSI cycles

Research question: Can previous reports of a decreased probability of success in stimulated IVF cycles with premature rise of progesterone, as determined by progesterone concentration on HCG day (PHCG), be confirmed? Design: Retrospective, observational, single-centre cohort study conducted on 5447 IVF and intracytoplasmic (ICSI) cycles carried out among 2192 patients between 2009 and 2015, with conventional ovarian stimulation. This large database was used to develop a non-linear mixed prognosis model of live birth rate (LBR) incorporating PHCG as a predictor. Results: In addition to known predictors (age, body mass index, anti-Mullerian hormone, type of infertility), PHCG was associated with a linear effect (OR 0.78 per Log[PHCG]ng/ml, 95% CI 0.611 to 0.997, P = 0.047) combined with a strong quadratic effect (OR 0.585 per Log(2) (PHCG)ng/ml, 95% CI 0.444 to 0.775, P < 0.001) resulting into a parabolic reverse-U curve. A significant interaction (P = 0.038) was found between PHCG and number of oocytes if three or less, but the effect of PHCG remains modest. For higher oocyte numbers, LBR rapidly increases with number of retrieved oocytes; however, LBR becomes more sensitive to PHCG as the number of oocytes increases. Higher live birth prognoses occur for optimal PHCG but are sharply reduced for lower or higher PHCG. Conclusions: Evidence is provided of an important negative effect of PHCG at lower and higher values, independent of oocyte number, thus defining appropriate ranges for fresh embryo transfer or freeze-all strategy. In poor responders, premature progesterone rise may be ignored, thus avoiding unnecessary cancellations or embryo freezing. Conversely, in higher responders, the negative effect of progesterone elevation is more pronounced, suggesting that freeze-all policy should be applied more widely.