A drop in serum progesterone from oocyte pick-up+3 days to+5 days in fresh blastocyst transfer, using hCG-trigger and standard luteal support, is associated with lower ongoing pregnancy rates

STUDY QUESTION: Do early- and mid-luteal serum progesterone (P-4) levels impact ongoing pregnancy rates (OPRs) in fresh blastocyst transfer cycles using standard luteal phase support (LPS)? SUMMARY ANSWER: A drop in serum P-4 level from oocyte pick-up (OPU) + 3 days to OPU + 5 days (negative delta P-4) is associated with a similar to 2-fold decrease in OPRs. WHAT IS KNOWN ALREADY: In fresh embryo transfer cycles, significant inter-individual variation occurs in serum P-4 levels during the luteal phase, possibly due to differences in endogenous P-4 production after hCG trigger and/or differences in bioavailability of exogenously administered progesterone (P) via different routes. Although exogenous P may alleviate this drop in serum P-4 in fresh transfer cycles, there is a paucity of data exploring the possible impact on reproductive outcomes of a reduction in serum P-4 levels. STUDY DESIGN, SIZE, DURATION: Using a prospective cohort study design, following the initial enrollment of 558 consecutive patients, 340 fulfilled the inclusion and exclusion criteria and were included in the final analysis. The inclusion criteria were: (i) female age <= 40 years, (ii) BMI <= 35 kg/m(2), (iii) retrieval of >= 3 oocytes irrespective of ovarian reserve, (iv) the use of a GnRH-agonist or GnRH-antagonist protocol with recombinant hCG triggering (6500 IU), (v) standard LPS and (vi) fresh blastocyst transfer. The exclusion criteria were: (i) triggering with GnRH-agonist or GnRH-agonist plus recombinant hCG (dual trigger), (ii) circulating P-4 > 1.5 ng/ml on the day of trigger and (iii) cleavage stage embryo transfer. Each patient was included only once. The primary outcome was ongoing pregnancy (OP), as defined by pregnancy & GE;12 weeks of gestational age. PARTICIPANTS/MATERIALS, SETTING, METHODS: A GnRH-agonist (n = 53) or GnRH-antagonist (n = 287) protocol was used for ovarian stimulation. Vaginal progesterone gel (Crinone, 90 mg, 8%, Merck) once daily was used for LPS. Serum P-4 levels were measured in all patients on five occasions: on the day of ovulation trigger, the day of OPU, OPU + 3 days, OPU + 5 days and OPU + 14 days; timing of blood sampling was standardized to be 3-5 h after the morning administration of vaginal progesterone gel. The delta P-4 (Delta P-4) level was calculated by subtracting the P-4 level on the OPU + 3 days from the P-4 level on the OPU + 5 days, resulting in either a positive or negative Delta P-4. MAIN RESULTS AND THE ROLE OF CHANCE: The median P-4 (min-max) on the day of triggering, day of OPU, OPU + 3 days, OPU + 5 days and OPU + 14 days were 0.83 ng/ml (0.18-1.42), 5.81 ng/ml (0.80-22.72), 80.00 ng/ml (22.91-161.05), 85.91 ng/ml (15.66-171.78) and 13.46 ng/ml (0.18-185.00), respectively. Serum P-4 levels uniformly increased from the day of OPU to OPU + 3 days in all patients; however, from OPU + 3 days to OPU + 5 days, some patients had a decrease (negative Delta P-4; n = 116; 34.1%), whereas others had an increase (positive Delta P-4; n = 220; 64.7%), in circulating P-4 levels. lthough the median (min-max) P-4 levels on the day of triggering, the day of OPU, and OPU + 3 days were comparable between the negative Delta P-4 and positive delta P-4 groups, patients in the former group had significantly lower P-4 levels on OPU + 5 days [69.67 ng/ml (15.66-150.02) versus 100.51 ng/ml (26.41-171.78); P < 0.001] and OPU + 14 days [8.28 ng/ml (0.28-157.00) versus 19.01 ng/ml (0.18-185.00), respectively; P < 0.001]. A drop in P-4 level from OPU + 3 days to OPU + 5 days (negative Delta P-4) was seen in approximately one-third of patients and was associated with a significantly lower OPR when compared with positive Delta P-4 counterparts [33.6% versus 49.1%, odds ratio (OR); 0.53, 95% CI; 0.33-0.84; P = 0.008]; this decrease in OPR was due to lower initial pregnancy rates rather than increased overall pregnancy loss rates. For negative Delta P-4 patients, the magnitude of Delta P-4 was a significant predictor of OP (adjusted AUC = 0.65; 95% CI; 0.59-0.71), with an optimum threshold of -8.73 ng/ml, sensitivity and specificity were 48.7% and 79.2%, respectively. BMI (OR; 1.128, 95% CI; 1.064-1.197) was the only significant predictor of having a negative delta P-4; the higher the BMI, the higher the risk of having a negative Delta P-4. Among positive Delta P-4 patients, the magnitude of delta P-4 was a weak predictor of OP (AUC = 0.56, 95% CI; 0.48-0.64). Logistic regression analysis showed that blastocyst morphology (OR; 5.686, 95% CI; 1.433-22.565; P = 0.013) and Delta P-4 (OR; 1.013, 95% CI; 0.1001-1.024; P = 0.031), but not the serum P-4 level on OPU + 5 days, were the independent predictors of OP. LIMITATIONS, REASONS FOR CAUTION: The physiological circadian pulsatile secretion of P-4 during the mid-luteal phase is a limitation; however, blood sampling was standardized to reduce the impact of timing. WIDER IMPLICATIONS OF THE FINDINGS: Two measurements (OPU + 3 days and OPU + 5 days) of serum P-4 may identify those patients with a drop in P-4 (approximately one-third of patients) associated with & SIM;2-fold lower OPRs. Rescuing these IVF cycles with additional P supplementation or adopting a blastocyst freeze-all policy should be tested in future randomized controlled trials.

Automated summary

A drop in serum P-4 level from oocyte pick-up (OPU) + 3 days to OPU + 5 days may result in a decrease in ongoing pregnancy rates. This decrease may be associated with lower initial pregnancy rates rather than increased overall pregnancy loss rates.