Estimating the net effect of progesterone elevation on the day of hCG on live birth rates after IVF: a cohort analysis of 3296 IVF cycles

STUDY QUESTION: What is the proper way of assessing the effect of progesterone elevation (PE) on the day of hCG on live birth in women undergoing fresh embryo transfer after in vitro fertilization (IVF) using GnRH analogues and gonad otrophins? SUMMARY ANSWER: This study indicates that a multivariable approach, where the effect of the most important confounders is controlled for, can lead to markedly different results regarding the association between PE on the day of hCG and live birth rates after IVF when compared with the bivariate analysis that has been typically used in the relevant literature up to date. WHAT IS KNOWN ALREADY: PE on the day of hCG is associated with decreased pregnancy rates in fresh IVF cycles. Evidence for this comes from observational studies that mostly failed to control for potential confounders. STUDY DESIGN, SIZE, DURATION: This is a retrospective analysis of a cohort of fresh IVF/intracytoplasmic sperm injection cycles (n = 3296) performed in a single IVF centre during the period 2001-2013. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients in whom ovarian stimulation was performed with gonadotrophins and GnRH analogues. Natural cycles and cycles where stimulation involved the administration of clomiphene were excluded. In order to reflect routine clinical practice, no other exclusion criteria were imposed on this dataset. The primary outcome measure for this study was live birth defined as the delivery of a live infant after 24 weeks of gestation. We compared the association between PE on the day of hCG (defined as P>1.5 ng/ml) and live birth rates calculated by simple bivariate analyses with that derived from multivariable logistic regression. The multivariable analysis controlled for female age, number of oocytes retrieved, number of embryos transferred, developmental stage of embryos at transfer (cleavage versus blastocyst), whether at least one good-quality embryo was transferred, the woman's body mass index, the total dose of FSH administered during ovarian stimulation and the type of GnRH analogues used (agonists versus antagonists) during ovarian stimulation. In addition, an interaction analysis was performed in order to assess whether the ovarian response (<6, 6-18, >18 oocytes) has a moderating effect on the association of PE on the day of hCG with live birth rates after IVF. MAIN RESULTS AND THE ROLE OF CHANCE: Live birth rates were not significantly different between cycles with and those without PE when a bivariate analysis was performed [odds ratio (OR): 0.78, 95% confidence interval (Cl): 0.56-1.09]. However, when a multivariable analysis was performed, controlling for the effect of the aforementioned confounders, live birth rates (OR: 0.68, 95% Cl: 0.48-0.97) were significantly decreased in the group with PE on the day of hCG. The number of oocytes retrieved was the most potent confounder, causing a 29.4% reduction in the OR for live birth between the two groups compared. Furthermore, a moderating effect of ovarian response on the association between PE and live birth rates was not supported in the present analysis since no interaction was detected between PE and the type of ovarian response (<6, 6-18, >18 oocytes). LIMITATIONS, REASONS FOR CAUTION:This is a retrospective analysis of data collected during a 12-year period, and although the effect of the most important confounders was controlled for in the multivariable analysis, the presence of residual bias cannot be excluded. WIDER IMPLICATIONS OF THE FINDINGS: This analysis highlights the need fora multivariable approach when researchers or clinicians aim to evaluate the impact of PE on pregnancy rates in their own clinical setting. Failure to do so might explain why many past studies have failed to identify the detrimental effect of PE in fresh IVF cycles.