Progesterone level in assisted reproductive technology: a systematic review and meta-analysis

Elevated progesterone (EP) or inadequate progesterone levels during ART cycle monitoring may lead to cycle cancellations or further progesterone supplementation, but practice varies. It remains controversial whether modifying clinical practice in the presence or absence of EP improves clinical outcomes. This systematic review aims to investigate if progesterone levels at different phases of fresh and frozen ART cycles influence pregnancy outcomes, in particular, that pertaining to day 3 versus day 5 embryo transfers. A systematic search of EMBASE, MEDLINE, CINAHL, PubMed, SCOPUS and Web of Science identified studies from the year 2000. We included studies with women undergoing fresh and frozen IVF/ICSI cycles; with extractable per woman data on pregnancy outcomes where serum progesterone measurement was performed. We excluded interventional studies that influence clinical decisions or studies with donor cycles. The Newcastle Ottawa Scale (NOS) was used to determine the risk of bias. The primary outcome was LBR, and the secondary outcomes were OPR, CPR and MR. PICOS study protocol was used to include non-randomized studies of interventions (NRSI). Analysis was done using RevMan5 and the studies were pooled using the DerSimonian and Laird for random effects meta-analysis. The study was registered with PROSPERO (registration ID CRD42022382423). 64 studies (N = 57,988 women) were included. In fresh cycles, there is no evidence that at baseline EP impacts LBR (P > 1.5 ng/ml, OR 0.76 [95% CI 0.39-1.49], 2 studies, N = 309) and CPR (P > 1.5 ng/ml, OR 0.81 [0.38-1.71], 2 studies, N = 309). EP at ovulation trigger is associated with a lower LBR (P > 1.0 ng/ml, OR 0.40 [0.23-0.69], 2 studies, N = 2805) and CPR (P > 1.0 ng/ml, OR 0.49 [0.42-0.58], 3 studies, N = 3323; P > 1.1 ng/ml, OR 0.66 [0.53-0.83], 2 studies, N = 2444; P > 1.2 ng/ml, OR 0.61 [0.39-0.96], 6 studies, N = 844; P > 1.5 ng/ml, OR 0.37 [0.17-0.81], 6 studies, N = 13,870; P > 2.0 ng/ml, OR 0.43 [0.31-0.59], 3 studies, N = 1949) with D3 embryo but not D5 [LBR (P > 1.5 ng/ml, OR 1.02 [0.74-1.39], 3 studies, N = 5174) and CPR (P > 1.5 ng/ml, OR 0.88 [0.67-1.14], 6 studies, N = 5705)]. We could not meaningfully meta-analyse studies on the day of egg collection in fresh cycles, embryo transfer in fresh cycles, at ovulation trigger or before ovulation in natural FET cycles and FET cycles due to significant study heterogeneity. We acknowledged the limitations on including studies post year 2000 and the exclusion of studies with multiple observations, which may result in inherent publication bias and some confounding factors uncontrolled for. In conclusion, in controlled ovarian stimulation, EP at baseline did not impact on LBR; EP at ovulation trigger is associated with a lower LBR for D3 but not for D5 embryo transfer. In FET cycles, as the studies were heterogeneous, we were unable to combine the data in a meaningful way. This review is sponsored by Complete Fertility and the Ministry of Health, Malaysia.