An editorial challenged the conclusions of a randomized clinical trial that found vaginal progesterone inferior to intramuscular administration in frozen embryo transfer cycles.

Published in F&S Reports, the editorial scrutinized the randomized clinical’s unexpectedly high pregnancy loss rates in the vaginal progesterone group and proposed potential confounding factors.

The original randomized clinical trial (RCT) compared three progesterone protocols: vaginal progesterone alone, IM progesterone alone, and a combined protocol. Pregnancy loss rates in the vaginal group included 33% biochemical and 22% clinical losses, totaling 50%. These findings led many programs to favor IM or combination protocols over vaginal-only administration. However, this rate contrasted starkly with historical data, where no prior studies reported comparable losses. The editorial emphasized the unprecedented nature of these results and questioned their plausibility.

The editorial highlighted physiological contradictions, noting that in natural cycles, the corpus luteum produced approximately 25 mg of progesterone daily, while the trial’s vaginal protocol administered 400 mg daily. Multiple studies have confirmed good absorption and unexpectedly high endometrial tissue levels with vaginal progesterone, making insufficient progesterone an unlikely explanation for the high pregnancy losses.

Interestingly, embryo implantation rates were consistent across all groups, with disparities arising only in pregnancy losses. The editorial proposed embryonic aneuploidy not evaluated as a result of the absence of preimplantation genetic testing (PGT), as a potential confounding factor. This hypothesis was linked to the unexplained disparities in pregnancy loss rates.

The analysis concluded that while the RCT’s findings were significant, they lacked sufficient evidence to deem vaginal progesterone inferior. The editorial recommended future studies involving euploid blastocysts to reduce the influence of aneuploidy. Additionally, it advocated for retaining vaginal progesterone within the standard of care and ensuring clear patient instructions in future trials.

This analysis underscored the importance of situating unexpected RCT results within the context of prior literature and biological plausibility. It illustrated how unrecognized variables could impact even well-designed studies, necessitating further investigation prior to revising clinical practices.