What is the optimal duration of progesterone administration before transferring a vitrified-warmed cleavage stage embryo? A randomized controlled trial.

What is the impact on clinical pregnancy rates when vitrified cleavage stage Day 3 embryos, warmed and cultured overnight to Day 4, are transferred on the 3rd or 5th day of progesterone administration in an artificial cycle?Clinical pregnancy rates are similar when transferring a vitrified-warmed cleavage stage Day 3 embryo after overnight culture on the 3rd or 5th day of progesterone administration.In artificially prepared cycles, progesterone supplementation is generally started 3 days before embryo transfer, although the optimal length of exposure to progesterone before frozen embryo transfer (FET) has not been established. However, in a natural cycle, serum progesterone levels start to rise before ovulation, due to the LH-stimulated production by the peripheral granulosa cells. Hence, it could be postulated that progesterone supplementation before embryo transfer in an artificial cycle should start earlier or even later.Prospective, randomized controlled trial, encompassing 300 patients who had embryos frozen on Day 3 and who underwent FET in an artificial cycle. Between 1 November 2012 and 31 December 2014, 300 patients were allocated to one of two groups as soon as endometrial thickness reached ≥7 mm on ultrasound after estrogen supplementation. A computer-generated randomization list was used, not concealed to the physicians. Each patient was enrolled into the study only once. FET was performed on the fifth day of progesterone supplementation in Group A, whereas in Group B, FET was performed on the third day of vaginal micronized progesterone administration. Embryos were thawed the day before transfer and after overnight culture, one or two Day 4 embryos were transferred.One hundred and fifty patients in Group A received 5 days of vaginal micronized progesterone tablets and one hundred and fifty patients in Group B received 3 days of micronized progesterone vaginally before FET. In Group A, 13 patients did not have an embryo transfer, compared with 12 patients in Group B.Clinical pregnancy rates did not differ significantly between both groups (37/137 (27.0%) in Group A versus 26/138 (18.8%) in Group B (OR 1.6 (CI 0.9-2.82), ITALIC! P = 0.11). However, early pregnancy loss was significantly higher in Group B (32/58 (55.2%)) compared with Group A (21/58 (36.2%)) (OR 0.46 (CI 0.22-0.97), ITALIC! P = 0.04).Although no statistically significant difference was seen in the primary outcome, the study may have been underpowered to detect smaller differences. The study was also not blinded and patients were aware of the exact duration of progesterone supplementation.This is the first randomized controlled trial to show that duration of progesterone administration in an artificially prepared FET cycle may modulate cycle outcome and that too short progesterone supplementation might be deleterious.No external finance was involved in this study. All authors declare to have no conflict of interest with regard to this trial.The trial was registered at clinicaltrials.gov (NCT01940653).9 September 2013.1 November 2012.