Timing of progesterone exposure for programmed frozen transfer of day 6 blastocysts: a systematic review and narrative synthesis

Frozen embryo transfer (FET) is used increasingly in assisted reproduction, but the optimal duration of progesterone exposure before programmed transfer of day 6 (D6) blastocysts remains uncertain. This systematic review with narrative synthesis evaluated reproductive outcomes after programmed D6 blastocyst FET according to the duration of progesterone exposure. PubMed/MEDLINE, Embase and Scopus were searched from inception to June 2025. Randomized and observational studies comparing 5, 6 and 7 full days of progesterone exposure in hormone replacement therapy cycles were eligible. The primary outcome was the live birth rate; secondary outcomes included clinical pregnancy rate, implantation rate, miscarriage rate, and, when reported, obstetric and neonatal outcomes. Evidence consisted mainly of retrospective cohort studies and propensity-score-matched analyses. The live birth rate after D6 blastocyst transfer was broadly comparable following 6 or 7 days of progesterone exposure across most cohorts, although one large D6 subgroup analysis reported a significant live birth advantage for 7 days of progesterone exposure. In the two studies providing direct D6 subgroup comparisons, 7 days of progesterone exposure was associated with a significantly lower miscarriage rate than 6 days of progesterone exposure, although these findings were retrospective and not replicated across all cohorts. Studies comparing 5 and 6 days of progesterone exposure yielded conflicting results. Overall, current evidence supports both 6 and 7 days of progesterone exposure as acceptable strategies for programmed D6 blastocyst FET, although individualized timing may be appropriate until randomized evidence becomes available.