Sublingual progesterone lozenges are a viable alternative to intramuscular progesterone-in-oil for programmed frozen embryo transfer cycles

Objective: To compare pregnancy outcomes and serum progesterone levels between women who took sublingual (SL) progesterone lozenges versus intramuscular (IM) progesterone-in-oil for endometrial preparation and luteal support in programmed frozen embryo transfer (pFET) cycles.

Design: Retrospective cohort study.

Subjects: All patients who underwent pFET of a single euploid good-quality blastocyst between January 2018 and April 2023 at a single fertility center.

Exposure: Patients received either compounded SL lozenges containing 200mg micronized progesterone three times per day or 50mg progesterone-in-oil daily. Both groups also took 100mg vaginal micronized progesterone three times per day.

Main outcome measures: Primary outcomes included clinical pregnancy (hCG ≥ 5 mIU/mL), ongoing pregnancy (pregnancy progressing past 8 weeks), live birth, and miscarriage. Secondary outcomes included progesterone levels at or one day prior to embryo transfer and at the time of the first pregnancy test.

Results: 1,951 pFET cycles were included, 1,030 (52.8%) who received IM progesterone and 921 (47.2%) who received SL progesterone. There were no significant differences between the IM and SL groups, respectively, in clinical pregnancy (69.5% vs. 74.4%, odds ratio (OR) 0.81, 95% confidence interval (CI) [0.61-1.09]), ongoing pregnancy (56.1% vs. 61.1%, OR 0.78, 95% CI [0.60-1.01]), live birth (50.1% vs. 57.0%, OR 0.85, 95% CI [0.64-1.14]), or miscarriage (25.1% vs. 24.1%, OR 1.24, 95% CI [0.87-1.79]) after controlling for age, race, estrogen preparation, endometrial thickness, physician performing the transfer, and number of prior embryo transfers (P>0.05, all). In the IM progesterone group, mean serum progesterone levels were significantly higher at the time of embryo transfer (41.6 ± 10.9 vs. 30.5 ± 15.7 ng/mL, P<0.01) and at first bhCG measurement (36.5 ± 11.5 vs. 29.4 ± 15.0 ng/mL, P<0.01) as compared to the SL group.

Conclusions: SL progesterone is a viable alternative to IM progesterone for pFET cycles that can minimize injection burden and likely improve patient satisfaction without compromising pregnancy outcomes. Progesterone levels, while slightly lower than the IM route, are in an acceptable range for luteal support.