The efficacy of subcutaneous versus vaginal progesterone for luteal phase support - a comparison in 723 blastocyst hormone replacement therapy frozen embryo transfer cycles

Abstract Study question Are ongoing pregnancy rates (OPRs) similar between subcutaneous (sc) progesterone (P) and vaginal P administration in hormone replacement therapy (HRT) frozen embryo transfer (FET) cycles? Summary answer The OPRs were similar between sc and vaginal P administration; however, 15.8% of patients in the vaginal group needed additional P as rescue therapy. What is known already There is a paucity of data comparing sc and vaginal P administration in HRT-FET cycles. In HRT-FET cycles, there seem to be marked interpersonal differences in serum progesterone (P4) levels following the same dose and route of P administration. Impaired reproductive outcomes have been reported when serum P4 levels are below a certain threshold (10 ng/ml) on the FET/FET-1 day; rescue with supplemental sc P in these cases might rectify reproductive outcomes. With sc P, only one study reported comparable OPRs in four quartiles of serum P4 on the day of FET in HRT cycles. Study design, size, duration A cohort study was conducted during December 2019-November 2022, including a total of 723 consecutive warmed blastocyst transfer cycles, employing HRT. Each patient was included only once. The inclusion criteria were female age ≤44 years old, BMI ≤40 kg/m2, and having available day-5/6 vitrified blastocyst(s) after warming. Pre-implantation genetic testing cycles for aneuploidy (PGT-A) were included, whereas PGT for monogenic disorders/structural re-arrangements and the presence of uterine anomalies were excluded from the study. Participants/materials, setting, methods Following estrogen priming, sc P 25 mg twice-daily (n = 249) or vaginal P gel 90 mg twice-daily (n=474) were administered. The serum P4 level was measured on the FET-1 day, i.e., day 5 of P supplementation. In patients with serum P4 levels <8.75 ng/ml on the FET-1-day, additional exogenous sc P, 25 mg/day (rescue), was provided. The primary outcome measure was OPR. A generalized additive model was performed to study functional relationships between P4 and OPR. Main results and the role of chance The mean circulating P4 levels on the FET-1 day were 26.1 ± 8.1 ng/ml and 13.8 ± 5.5 ng/ml in the sc P and vaginal P gel groups, respectively (p < 0.001). In the vaginal P group, 15.8 % of patients needed sc P rescue, whereas no patient required rescue in the sc P group. All unadjusted reproductive outcome measures, including positive hCG per embryo transfer, implantation, clinical pregnancy, pre-clinical loss, miscarriage rates, and OPRs, were comparable between the sc P and vaginal P gel groups. After P rescue, when logistic regression analysis was performed to delineate the independent predictor(s) of ongoing pregnancy, only female age, number of blastocysts transferred, blastocyst morphology, and PGT-A were found to be the significant predictors. Importantly, sc P administration, necessitating no rescue, provided similar OPRs (adjusted OR = 1.22 95% CI:0.87-1.80) compared to vaginal P, in which rescue was needed in 15.8% of the patients. The impact of serum P4 levels on adjusted reproductive outcome measures was evaluated by percentiles (<10th, 10–49th, 50–90th, and >90th percentiles). All serum P4 percentiles had similar OPRs, and no significant association was observed between serum P4 levels and OPRs in both sc and vaginal P (with rescue if needed) groups. Limitations, reasons for caution Cohort study, lack of cost and side-effect analyses. Wider implications of the findings Subcutaneous P 25 mg twice-daily secures a serum P4 above 8.75 ng/ml, whereas additional exogenous P (rescue) was needed in 15.8% of patients receiving vaginal P administration only. The OPR was similar between the sc P alone and vaginal P groups after sc P rescue of the vaginal group. Trial registration number Not applicable