Subcutaneous Progesterone versus Vaginal Progesterone Supplemented with Intramuscular Progesterone Every Third Day in...

To compare ongoing pregnancy rates between subcutaneous progesterone and vaginal progesterone supplemented with intramuscular progesterone every third day in programmed frozen embryo transfer cycles.

Retrospective cohort study.

Six hundred twenty patients undergoing their first vitrified-warmed blastocyst transfer with a programmed protocol at a single tertiary center between March 2018 and June 2023; no exclusion criteria were applied.

Following 10 to 12 days of estradiol valerate 6 mg/day, 451 patients received subcutaneous progesterone 25 mg every 12 hours, and 169 patients received vaginal progesterone gel 90 mg every 12 hours supplemented with intramuscular progesterone 50 mg every third day (days 1, 4, and 7 of progesterone start). The regimens were used during sequential, nonoverlapping calendar periods.

Ongoing pregnancy rate. Serum progesterone was measured on the fifth day of progesterone administration (one day before transfer), 4 to 5 hours after the morning dose. Associations between serum progesterone and ongoing pregnancy were evaluated using regimen-specific percentile categories and continuous modeling. Adjusted risk ratios (aRRs) were estimated using modified Poisson regression.

Ongoing pregnancy rates were 53.6% versus 54.4% in the subcutaneous and vaginal plus intramuscular groups, respectively (crude risk difference: -0.9 percentage points; 95% CI: -9.5 to 7.9). After covariate adjustment, standardized risks were 53.6% and 56.2%, respectively (adjusted risk difference: -2.6 percentage points; 95% CI: -12.0 to 6.7; aRR: 0.95; 95% CI: 0.81-1.13). Median serum progesterone was 23.48 ng/mL (interquartile range 18.72-29.46) versus 22.90 ng/mL (interquartile range 18.50-29.40), respectively (p=0.543). Neither the percentile-based analyses nor continuous modeling identified a clear association between serum progesterone concentration and ongoing pregnancy within the observed ranges.

No statistically significant difference in ongoing pregnancy was observed between subcutaneous progesterone 25 mg every 12 hours and vaginal progesterone 90 mg every 12 hours supplemented with intramuscular progesterone 50 mg every third day. Serum P₄ distributions overlapped between groups. However, the study design and statistical imprecision preclude causal inference and conclusions of equivalence or non-inferiority.